Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[BH4-].[Na+].C(OCC)(=O)C>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[CH:15]([OH:17])[CH3:16]
Reactant: CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1cc(-c2cccc(Cl)c2)ccc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
To a solution of 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone (see example 35, 0.15 g, 0.61 mmol) in anhydrous methanol was added sodium borohydride (0.07 g, 1.03 mmol) at room temperature (rt) under nitrogen. After 15 minutes, the reaction mixture was treated with ice-water. Ethyl acetate (30 mL) was then added, the organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried over MgSO4. After removal of solvent, the residue obtained was crystallized from toluene to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanol as a white solid (0.087 g, 58%): 1H-NMR (DMSO-d6) δ 7.55 (t, 1H, J=1.4 Hz), 7.50 (d, 1H, J=7.8 Hz), 7.44 (d, 1H, J=2.1 Hz), 7.39 (t, 1H, J=8.2 Hz), 7.31-7.21 (m, 2H), 6.68 (d, 1H, J=8.1 Hz), 5.25 (s, 2H), 5.20 (m, 1H), 4.83 (m, 1H), 1.35 (d, 3H, J=8.8 Hz); MS (EI) m/z 247 (M+).
Reaction SMILES: [CH3:1][CH:2]([NH2:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:18][N:19]=[C:20]=[O:21]>C(Cl)Cl>[CH3:1][CH:2]([NH:17][C:20]([NH:19][CH3:18])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CN=C=O
Reactant: CCCCCCCCCCCCCCC(C)N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCC(C)NC(=O)NC

Procedure:
38.6 g (0.135 mole) beta-hexadecylamine in 60 ml methylene chloride was reacted with 9.6 ml methyl isocyanate in 15 ml methylene chloride in accordance with the procedure in Example 4, yielding a white solid reaction product.
Reaction SMILES: C(OCC)(=O)C(C1C=CC=CC=1)=C.C(OC)(=O)C(C1C=CC=CC=1)=C.[C:26]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:38](OCC)(=[O:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40].C([O-])C.[Na+]>>[O:44]=[C:38]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)Cc1ccccc1
Agent: C=C(C(=O)OC)c1ccccc1
Agent: C=C(C(=O)OCC)c1ccccc1
Agent: CC[O-]
Product: CCOC(=O)C(=O)C(C(=O)OCC)c1ccccc1

Procedure:
Ethyl atropate with a methyl atropate content not exceeding 0.05% can be obtained in a relatively complicated, two-stage process (Helv. Chim. Acta 30, 1349 (1947)) as long as the starting materials do not contain more than 0.05% of methyl compounds. This process involves ethyl phenylacetate being condensed with diethyl oxalate in the presence of sodium ethanolate to give diethyl 2-oxo-3-phenylsuccinate, Na salt. Subsequent reaction with formaldehyde in the presence of potassium carbonate results in ethyl atropate with a methyl ester content not exceeding 0.05%.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:16][S:17][CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20].C(OCl)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:4](=[O:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:12][CH:13]=[CH:14][C:15]=1[CH:18]([S:17][CH3:16])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20]
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: CSCC(=O)N(C)C
Agent: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC(C(=O)N(C)C)c1cccc(C(=O)c2ccccc2)c1N
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A solution of 29.6 g (0.15 mole) of 2-aminobenzophenone in 350 ml of methylene chloride was cooled to -70° C. and 20.0 g (0.15 mole) of 2-methylthio-N,N-dimethylacetamide was added. To the mixture (-70° C.) was added dropwise a solution of 17.2 g (0.15 mole) of 95% t-butylhypochlorite in 30 ml of methylene chloride. The temperature was maintained at or below -65° C. for 1.5 hr, then 15.1 g (0.15 mole) of triethylamine was added rapidly. The solution was allowed to warm to room temperature and was washed with water. The organic solution was concentrated and the residue crystallized when mixed with isopropyl ether. The solid was recrystallized from isoproyl alcohol to give 39.8 g (81%) bright yellow crystals, m.p. 153°-155° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1.[N:37]12[CH2:44][CH2:43][N:40]([CH2:41][CH2:42]1)[CH2:39][CH:38]2[CH2:45][NH2:46].C(N(CC)C(C)C)(C)C.O>CN1CCCC1=O>[N:37]12[CH2:44][CH2:43][N:40]([CH2:41][CH2:42]1)[CH2:39][CH:38]2[CH2:45][NH:46][C:2]1[N:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH2:23][CH2:22][C@@H:21]([NH:24][C:25]([C:27]4[NH:28][C:29]([CH3:34])=[C:30]([Cl:33])[C:31]=4[Cl:32])=[O:26])[C@@H:20]([O:35][CH3:36])[CH2:19]3)[S:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:6][CH:7]=1
Reactant: NCC1CN2CCN1CC2
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)nc1-c1cnc(Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1cnc(NCC2CN3CCN2CC3)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 20.7 %

Procedure:
Ethyl 4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate (Example 59, 330 mg, 0.57 mmol) was added to a solution of 1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88 mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl 2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirred for 20 h at 80° C. The reaction mixture was cooled to room temperature, poured into water (40 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduce pressure to yield crude product which was purified by flash column chromatography over silica gel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl 4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate as an off-white solid.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:25][SH:26].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:17][S:14]([NH:13][C:11]1[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:6]2[C:7](=[O:8])[CH:2]([S:26][CH3:25])[CH2:3][O:4][C:5]=2[CH:12]=1)(=[O:16])=[O:15]
Reactant: CS
Reactant: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)C(Br)CO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSC1COc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
In 50 ml of methylene chloride were dissolved 2.06 g of 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one and 480 mg- of methylmercaptan. Thereto was added 2.02 g of triethylamine at 0°-5° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was introduced into 30 ml of water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 50 : 1 mixture of toluene and ethyl acetate) to obtain 900 mg (yield: 47.4%) of 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18]([CH:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:33][CH2:34][CH2:35][CH3:36])[N:14]([CH2:15][CH2:16][NH:17][C:18](=[O:19])[CH:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)C(N)CC(C)C

Procedure:
1,1-Dimethylethyl N-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate (0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) and heated on a steam bath for 30 minutes. The reaction mixture was allowed to cool and then it was made basic with 10% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.15 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentamide as a white solid, m.p. 60-65° C. Analysis: Calculated for C21H31N7O: % C, 63.27; % H, 7.86; % N, 24.66; Found: % C, 62.27; % H, 7.67; % N, 24.77. HRMS (EI) calcd for C21H31N7O (M+) 397.2590 found 397.2582.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[CH3:11][N:12]1[C:16]2[CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=[CH:20][C:15]=2[O:14][C:13]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]2[O:14][C:13](=[O:30])[N:12]([CH3:11])[C:16]=2[CH:17]=1)(=[O:10])[CH3:9]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(=O)c1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Temperature: 90 °C
Yield: 55.2 %

Procedure:
A mixture of 1-(3-bromopyridin-4-yl)ethanone (50 mg, 0.250 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2(3H)-one (68.8 mg, 0.250 mmol), polymer bound PalladiumTetrakis (56.8 mg, 6.25 μmol) and sodium carbonate (250 μl, 0.500 mmol) in toluene (1 mL) and ethanol (1 mL) was heated to 90° C. in microwave for 45 min. After filtration through a pad of Na2SO4, the solvent was removed in vacuum. The residue was purified by flash column (MeOH—CH2Cl2, v/v, 1%-1.5%) and yielded colorless solid (37 mg). ESI-MS m/z: 269.0 [M+1]+, Retention time 1.03 min; 1H NMR (400.3 MHz, CDCl3): δ 2.13 (s, 3H), 344 (s, 3H), 6.95 (d, J=1.48 Hz, 1H), 7.07 (dd, J=8.2, 1.68 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.37 (d J=5 Hz, 1H), 8.69 (s, 1H), 8.73 (d, J=5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([NH2:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C.CN([CH:25]=[O:26])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9]([CH3:11])([CH3:10])[NH:12][C:25]2=[O:26])=[CH:4][CH:5]=1
Reactant: CC(C)(N)c1ccc(F)cc1Br
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)NC(=O)c2cc(F)ccc21
Temperature: 130 °C
Reaction time: 16 h
Yield: 8.6 %

Procedure:
A mixture of 1-(2-bromo-4-fluoro-phenyl)-1-methyl-ethylamine (1.5 g, 6.52 mmol), Pd(dppf)Cl2 (0.15 g), DIPEA (2.52 g, 19.6 mmol) in DMF (20 mL) was stirred in an autoclave under 2 MPa of CO (g) at 130° C. for 16 hours. After it was cooled to room temperature, the reaction mixture was diluted with EtOAc (300 mL). The organic layer was washed with brine, filtered, and concentrated under reduced pressure to give a crude product which was purified by chromatography to give the title compound (100 mg, yield 8.6%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>C(O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cncc(Cl)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cncc(Cl)c1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To a stirred solution of ethyl (2E)-3-(5-chloropyridin-3-yl)prop-2-enoate (338 mg, 1.6 mmol) [CAS number 163083-45-2] in dry ethanol (10 mL) at 0° C. under an atmosphere of argon was added solid sodium borohydride (67 mg, 1.75 mmol). The reaction mixture was allowed to warm to room temperature and stirred for four hours, whereupon additional sodium borohydride (67 mg, 1.75 mmol) was added. After stirring for an additional eighteen hours, saturated aqueous ammonium chloride solution (5 mL) was added. Volatiles were removed in vacuo, and the residue partitioned between water (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo. Flash chromatography (silica gel, 20% to 100% ethyl acetate in hexane) gave the title compound (132 mg, 0.62 mmol) and the saturated alcohol (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:21])[N:7]=[C:8]([NH:10]C(OCC2C=CC=CC=2)=O)[CH:9]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:21])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)nn1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)nn1C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
5-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carbDxylic acid methyl ester (643, 2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10% palladium on carbon (500 mg). The mixture was stirred under an atmosphere of hydrogen for three hours. The mixture was filtered through Celite and the solvent was removed under reduced pressure to give the desired compound (644, 1.2 g, 98%). (ESI) [M+H+]+=156.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][C:13]1=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COCCN1c1ccc([N+](=O)[O-])cc1F
Temperature: 140 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of 1,2-difluoro-4-nitrobenzene (7.95 g, 50.0 mmol), morpholin-3-one (5.06 g, 50.0 mmol) and K2CO3 (13.82 g, 100 mmol) in DMF (80 mL) was stirred at 140° C. overnight. The mixture was cooled to rt and filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a yellow solid (5.00 g, 42%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]2[N:16]([CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)[CH:17]=[N:18][C:14]=2[CH:13]=[C:12]([Cl:27])[N:11]=1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:17]1[N:16]([CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)[C:15]2[C:10]([Cl:9])=[N:11][C:12]([Cl:27])=[CH:13][C:14]=2[N:18]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 25 °C

Procedure:
N-bromosuccinimide (3.28 g, 18.4 mmol) was added to a solution of 4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (Preparative Example 2.3, 5 g, 16.8 mmol) stirring in degassed chloroform (168 mL) at room temperature. The reaction was heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with dichloromethane, and washed with saturated aqueous sodium thiosulfate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C14H16BrCl2N3 [M+H]+ 378. found 378.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1(B(O)O)[C:22]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:21]2[C:22]3[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc2c1ccc1ccccc12
Reactant: Brc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc3ccccc3c3ccccc23)c1
Yield: 84.8 %

Procedure:
Under an atmosphere of argon, 3-bromoiodobenzene (7.0 g, 25 mmole), phenanthreneboronic acid (5.0 g, 23 mmole) and tetrakis-(triphenylphosphine)palladium(0) (0.5 g, 0.43 mmole, 1.7% Pd) were dissolved into toluene (100 ml). To the obtained solution, an aqueous solution of sodium carbonate (7.3 g, 69 mmole, 3 eq/35 ml) was added and the resultant solution was heated under refluxing for 10 hours and left standing for one night. The formed organic layer was separated, washed with a saturated aqueous solution of sodium chloride (50 ml) and dried with anhydrous magnesium sulfate. Then, the solvent was removed by distillation and a yellow oil was obtained. The obtained oil was purified by the column chromatography (silica gel/hexane, hexane+3% dichloromethane and hexane+5% dichloromethane, successively) and white needle crystals (6.5 g, 85%) were obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (299 mg, 7.48 mmol) was added to a stirred solution of 4-bromo-6-fluoro-1H-indole (800 mg, 3.74 mmol) in DMF (20 ml) that had been cooled in an ice bath to 0° C. and placed under nitrogen. The mixture was stirred for 5 mins before 4-nitrobenzenesulfonyl chloride (911 mg, 4.11 mmol) was added. The mixture was stirred at 0° C. for 1 hour. The resultant orange/brown solution was poured into stirring water (40 ml). The mixture was rapidly stirred for 30 mins. The resulting brown suspension was collected by filtration, washed with water and dried in a vacuum oven at 50° C. overnight to give a pale brown solid, which was purified by Flashmaster II, on a silica cartridge (100 g) using a gradient of ethylacetate and cyclohexane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].CCN(CC)CC.[CH2:17](N)[CH2:18][CH2:19][CH3:20]>CCCCO>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C:2]=1[NH2:1]
Reactant: CCCCN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCCCc1ncnc(Cl)c1N
Reaction time: 16 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in n-BuOH was treated with Et3N (1.2 mmol) and n-Butylamine (1.0 mmol) at 80 C. After 16 h, solvent was removed under reduced pressure. The residue was dissolved in EtOAc, the organic layer washed with water and then dried (MgSO4). Filtration and removal of solvent gave 6-chloro-5-amino-4-butyl pyrimidine as a brown solid. Rf=0.5 in 1:1 EtOAc:hexane. 1H NMR (CDCl3) δ 8.07 (s, 1H), 4.88 (br s, 1H), 3.49 (m, 2H), 3.35 (br s, 2H), 1.6 (m, 2H), 1.44 (m, 2), 0.95 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: CC(C)=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C3CCNCC3)cn2)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCC(c2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 6-chloro-2-methyl-4-(5-(piperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (200 mg, 625 μmol, Eq: 1.00) and acetone (799 mg, 1.01 ml, 13.8 mmol, Eq: 22) in MeOH (5 ml) was added sodium cyanoborohydride (39.3 mg, 625 μmol, Eq: 1.00) and acetic acid (656 mg, 625 μl, 10.9 mmol, Eq: 17.5). The reaction mixture stirred under N2 for 18 h. Additional acetone (1 ml) was added, followed by THF (3 ml). The reaction mixture continued stirring under N2 for 2 h. Additional sodium cyanoborohydride (19.7 mg, 313 μmol, Eq: 0.50) was added. The mixture stirred for 4 h. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give 6-chloro-4-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (220 mg, 97%). LC/MS-ESI observed [M+H]+ 362.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: O=Cc1cccc(O)c1
Reactant: BrCCCCCCCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 2-(8-bromooctyl)-1,3-dioxolane (5 g, 18.85 mmol) in dimethyl formamide (100 mL) was added 3-hydroxybenzaldehyde (2.37 g, 19.42 mmol) and potassium carbonate (5.37 g, 38.83 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (4.66 g, 78%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:20]([CH2:22][NH2:23])[OH:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:21][CH2:20][CH2:22][NH:23][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: NCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCO)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of Example 9 (110 mg; 0.33 mmol; 1 eq.), is dissolved in DCM (10 ml). Ethanolamine (39.9 mg; 0.65 mmol; 2 eq.) and DIEA (0.17 ml; 0.98 mmol; 3 eq.) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, Compound (11) is obtained as white-off solid (36.5 mg; 30%). 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.43 (s, 3H), 2.91 (m, 2H), 3.41 (m, 2H), 4.72 (t, J=6 Hz, 1H), 7.21 (d, J=4.5 Hz, 1H), 7.54 (d, J=4.5 Hz, 1H), 7.88 (br s, 1H), 12.25 (br s, 1H). M−(ESI): 360.11; M+(ESI): 362.06. HPLC, Rt: 2.36 min (purity: 97.5%).