Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][NH:5][CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][N:5]([CH2:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(C)s1)OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(CN(Cc1ccc(C)s1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 0 °C
Reaction time: 20 h

Procedure:
Crude (2,2-dimethyloxy-ethyl)-(5-methyl-thiophen-2-ylmethyl)-amine (1) (43.41 g ˜75% pure, 0.15 mol) was dissolved in EtOAc (150 mL) resulting in a yellow solution. Triethylamine (22 mL, 0.16 mol) was added. The mixture was cooled to 0° C. in ice bath. p-Toluenesulfonyl chloride (29.68 g, 0.16 mol) was added in small portions keeping the temperature below 15° C. After addition was complete the mixture was left in ice bath and allowed to slowly warm to room temperature and stirred for 20 hrs. The milky-yellow mixture was diluted with EtOAc (300 mL) and washed with water (2×400 mL), 1 M HCl (2×400 mL), water (1×400 mL), sat NaHCO3 (1×400 mL), and brine (1×400 mL), dried (MgSO4) and condensed to provide the title compound as a reddish-yellow liquid, 50.56 g. Product was not purified.
Reaction SMILES: [O:1]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.O>[O:1]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 735.5 %

Procedure:
To a solution of ethyl 2-phenoxypropanoate (1.8 g, 0.9 mmol) in EtOH (16 ml) was added a solution of NaOH (0.44 g, 1.1 mmol) in H2O (4 ml) at 25° C. The mixture was stirred for 30 min before being concentrated. The residue had water (20 mL) added and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (1.1 g, 73.3%) as a white solid which was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C.[BH4-].[Na+]>O1CCCC1>[CH2:9]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Brc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromo aniline (5 g, 29 mmol), benzaldehyde (3.24 ml, 32 mmol) and acetic acid (2.49 ml, 44 mmol) in dry tetrahydrofuran (50 ml) was stirred at room temperature for 3 hrs. Sodium borohydride (2.755 g, 73 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was quenched with water (100 ml) and extracted with dichloromethane (3×100 ml). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo. HPLC retention time 7.7 min. Mass spectrum (ES+) m/z 263 (M+H)
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.[ClH:24]>C(O)C.[Pd]>[ClH:24].[NH2:1][CH:4]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[S:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C1c2ccccc2Sc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C1c2ccccc2Sc2ccccc21

Procedure:
Ethyl α-nitro-9H-thioxanthene-9-acetate (4.4 g, 13.4 mmol) is hydrogenated in 200 mL of ethanol and 13.5 mL of concentrated hydrochloric acid with 1.0 g of 20% palladium on carbon (51 psi, 28 hours). The filtered solution is stripped of solvent and the residual solid washed with dichloromethane, dried at 45° C./2 mm Hg. This gives 3.66 g of the title compound; mp 238°-240° C. An additional crop (0.41 g) is obtained after cooling the mother liquor; mp 233°-236° C.
Reaction SMILES: [CH2:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1COCC1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([C:35]2([CH:40]=[CH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: COc1cc(OC)cc(C2(C=O)CCCC2)c1
Reactant: CCCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To the above slurry of (butylmethylene) triphenylphosphorane at 10° C. under an argon atmosphere was added dropwise a solution of (3,5-dimethoxyphenyl)cyclopentane carboxaldehyde (1 equiv.) in dry THF (0.21M). The reaction was stirred for 45 min and upon completion was quenched by the addition of saturated aqueous ammonium chloride. The organic layer was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure to give an oil. The crude product was purified through a short column of silica gel using 5% diethyl ether-petroleum ether as eluent to afford the title compound in 96% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:21])[C:17]([NH:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:20][NH:19][C:17](=[O:18])[CH:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:21]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CNC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A suspension of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.29 g, 27.3 mmol), 2-bromo-N-methylpropanamide (9.05 g, 54.5 mmol) and potassium carbonate (5.65 g, 40.9 mmol) in 136 ml acetone was refluxed for 68 hours. The white suspension was filtered through Celite with acetone washes; and the filtrate was concentrated and purified via silica gel chromatography (80 mm; 1 L 65% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[C:3]([NH2:8])[CH:2]=1.[CH2:9]([O:11][CH2:12][CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]=[C:33]=[S:34])[CH2:26][CH2:25]1)[CH3:10]>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[NH:8][C:33]([NH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:15]2[N:14]([CH2:13][CH2:12][O:11][CH2:9][CH3:10])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH2:25][CH2:26]1)=[S:34]
Reactant: Nc1ccncc1N
Reactant: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCNC(=S)Nc3cnccc3N)CC2)nc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 3.8 parts of 3,4-pyridinediamine, 13.1 parts of 3-(2-ethoxyethyl) -2-[[4-(2-isothiocyanatoethyl)-1-piperazinyl]methyl]-3Himidazo[4,5-b]-pyridine and 135 parts of tetrahydrofuran was stirred overnight at reflux temperature. The whole was evaporated, yielding 16.9 parts (100%) of N-(4-amino-3-pyridinyl)-N'-[2-[4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazinyl]ethyl]thiourea as a residue (compound 122).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[S:13](Cl)(=[O:15])=[O:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:28][CH:27]([NH2:29])[CH2:26]2)=[CH:20][CH:19]=1>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:25]2[CH2:26][CH:27]([NH:29][S:13]([C:9]3[S:8][CH:12]=[CH:11][CH:10]=3)(=[O:15])=[O:14])[CH2:28]2)=[CH:20][CH:19]=1
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cccs1
Temperature: 25 °C
Reaction time: 68 h
Yield: 66.2 %

Procedure:
69.3 mm3 of triethylamine and 110 mg of thien-2-ylsulfonyl chloride are successively added, at room temperature and under an argon atmosphere, to a solution of 61.4 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 3 cm3 of dichloromethane. After stirring for 68 hours at room temperature, the reaction mixture is introduced into a Bond Elut® SCX cartridge (3 cm5/500 mg) , eluting successively with twice 2 cm3 of dichloromethane and then twice 2 cm3 of a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is dissolved in 5 cm3 of dichloromethane, washed with three times 3 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). 60 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}thien-2-ylsulfonamide are thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.77 (split t, J=7 and 2 Hz: 2H); 3.40 (split t, J=7 and 2 Hz: 2H); 4.06 (mt: 1H); 4.21 (s: 1H); from 4.85 to 5.25 (broad unresolved complex: 1H); 7.06 (t, J=4.5 Hz: 1H); from 7.15 to 7.35 (mt: 8H); 7.58 (mt: 2H)].
Reaction SMILES: C(OC([C:17]1[N:18]2[CH:21]([O:22][CH2:23][C:24]=1[CH:25]=[CH:26]N(C)C)[CH:20](NC(=O)C(=NOC)C1N=C(NC(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)SC=1)[C:19]2=[O:62])=O)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C(OCC)(=[O:66])C>>[O:62]=[C:19]1[N:18]2[CH:21]([O:22][CH2:23][C:24]([CH2:25][CH:26]=[O:66])=[CH:17]2)[CH2:20]1
Reactant: CCOC(C)=O
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CN(C)C)COC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Product: O=CCC1=CN2C(=O)CC2OC1

Procedure:
A solution of the E form of the syn isomer of 2-benzhydryloxycarbonyl-3-(2-dimethylaminovinyl)-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene (1.05 g) in ethyl acetate (10 cc) is stirred vigorously for 1 hour at 20° C., in the presence of a 1 N solution of hydrochloric acid (5 cc). The mixture is separated by decantation and the organic phase is washed with a saturated solution of sodium bicarbonate (10 cc), distilled water (10 cc) and a saturated solution of sodium chloride (10 cc). The ethyl acetate phase is dried over anhydrous magnesium sulphate and filtered and the filtrate is concentrated to dryness at 30° C. under reduced pressure (20 mm Hg; 2.7 kPa). This yields the syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido[-8-oxo-3-(2-oxoethyl)-5-oxa-1-azabicyclo[4.2.0]-oct-2-ene (1.00 g) in the form of a hard yellow foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].C([O-])(=O)C.[Na+]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[C:4]([CH3:15])[N:3]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: Cc1nc(Cl)c2cc([N+](=O)[O-])ccc2n1
Reactant: COc1ccc(N)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc(Nc2nc(C)nc3ccc([N+](=O)[O-])cc23)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-methyl-6-nitro-quinazoline (80 mg, 0.36 mmol), 3,4-dimethoxy-aniline (54.8 mg, 0.36 mmol) and sodium acetate (35.2 mg, 0.43 mmol) similar to example 20 to give 109 mg (89.5%) of yellow solids. 1H NMR (CDCl3): 8.87 (d, J=2.7 Hz, 1H), 8.56 (dd, J=2.4 Hz, J=9.0 Hz, 1H), 7.91 (d, J=9.0 Hz, 1H), 7.63-7.61 (m, 2H), 7.28-7.24 (m, 1H), 6.94 (d, J=8.7 Hz, 1H), 3.96 (s, 3H)), 3.93 (s, 3H), 2.71 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.CO.C(O)(=O)C.[BH3-]C#N.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C3CCN(C)CC3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 24 %

Procedure:
To a stirred solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide (1 equiv.) and 1-methylpiperidin-4-one (1.5 equiv.) in methanol (5 mL per 0.3 mmol), acetic acid (1 equiv.) was added and reaction stirred at room temperature for 5 h. Then NaBH3CN (1 equiv.) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the residue purified by column chromatography (24% yield). LCMS: 555.15 (M+1)+; HPLC: 92.59% (@ 254 nm) (Rt; 4.143); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.60 (t, 1H, J=5.2 Hz), 8.35 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 5.88 (s, 1H), 4.63-4.68 (m, 1H), 4.32 (d, 2H, J=4.8 Hz), 2.97 (d, 2H, J=11.6 Hz), 2.79 (d, 2H, J=10.8 Hz), 2.22-2.40 (m, 3H), 2.19 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.99-2.08 (m, 2H), 1.81-1.88 (m, 4H), 1.69 (d, 2H, J=11.2 Hz), 1.43-1.48 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:25])[CH2:8][NH:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:11])=[O:5].[Cl:32][C:33]1[CH:44]=[CH:43][C:36](/[CH:37]=[CH:38]/[S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:34]=[CH:35][C:36](/[CH:37]=[CH:38]/[S:39]([NH:2][CH2:3][C:4]([NH:6][CH:7]([C:24]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:25])[CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[O:5])(=[O:41])=[O:40])=[CH:43][CH:44]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Reactant: NCC(=O)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Agent: Cl
Product: O=C(CNS(=O)(=O)/C=C/c1ccc(Cl)cc1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Yield: 16 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-amino-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide hydrochloride salt was reacted with (E)-4-chlorostyrylsulphonyl chloride to give 2-[(E)-4-chlorostyrylsulphonamido]-N -[1-piperidinocarbonyl-2-{1-(4-pyridyl)piperidin-4-ylcarbonylamino]ethyl}acetamide as a gum (0.1 g, 16%);
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=1>>[CH3:1][N:2]1[C:6]([O:7][C:18]2[N:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[N:19]=2)=[C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(O)c1Sc1ccc(Cl)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(Oc2c(Sc3ccc(Cl)cc3)c(C)nn2C)n1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A mixture of 0.255 g (1.00 mmol) of 1,3-dimethyl-4-(4-chlorophenylthio)-5-hydroxypyrazole and 0.43 g (3.00 mmol) of 2-chloro-4,6-dimethylpyrimidine was heated on a bath of which temperature was 130° C. for 3 hours with stirring. After completing the reaction, the reaction mixture was purified by means of silica gel column chromatography (developing solution: ethyl acetate) to give 0.308 g of 1,3-dimethyl-4-(4-chlorophenylthio)-5-(4,6-dimethylpyrimidine-2-yloxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[CH:4][C:3]=1[F:29].[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[CH2:20]([O:19][C:17]([N:15]1[CH2:16][C:11]2[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[C:3]([F:29])[CH:4]=3)=[N:13][C:12]=2[CH2:14]1)=[O:18])[CH3:21]
Reactant: CCN=C=O
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)c(F)c3)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)cc1F
Yield: 22 %

Procedure:
Method as described for example 85 using (S)-ethyl 2-(4-amino-3-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 19) and ethyl isocyanate as starting materials. The solvent was removed in vacuo and the residue purified by prep HPLC (high pH) yielding the title compound (10 mg, 0.021 mmol, 22%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:6](Cl)([Cl:9])([Cl:8])=[S:7]>CCOCC>[Cl:8][P:6]([Cl:9])([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[S:7]
Reactant: C1CCNC1
Reactant: S=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: S=P(Cl)(Cl)N1CCCC1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 43.4 mL (0.52 mol) of pyrrolidine in 50 mL of ether was added dropwise to a stirred solution of 116 mL (1.04 mol) of thiophosphoryl chloride in 200 mL of ether at 0° C. (ice bath) under an argon atmosphere. After the addition was completed, the resultant slurry was slowly warmed to room temperature overnight. A trace of pyrrolidinium hydrochloride was removed by filtration and the filtrate was concentrated under vacuum to provide 84.5 g of a clear oil. A portion of this oil (40 g) was distilled at 80° C. (0.25 mm) to provide 18.1 g of the desired dichloride as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:29])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:37][CH2:38][C@H:39]1[CH2:43][O:42][C:41]([CH3:45])([CH3:44])[O:40]1>CN(C=O)C>[CH3:44][C:41]1([CH3:45])[O:40][C@@H:39]([CH2:38][CH2:37][O:13]/[N:12]=[C:11]2\[NH:10][C@@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=3)[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:29])[C:5]\2=3)[CH2:43][O:42]1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/O)N2)n1
Reactant: CC1(C)OC[C@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC[C@H]3COC(C)(C)O3)N2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
To a solution of (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (86g or Compound 61, 10.0 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs2CO3 (12.2 mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperature for 30 minutes. Then, (5)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (86d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirred overnight. LCMS showed complete consumption of starting material. The reaction mixture was poured onto crushed ice and the resulting solid was filtered, rinsed with cold water, and dried to afford (R,Z)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (86h, 8.2 mg, 63%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (s, 3H) 1.39 (s, 3H) 1.91-2.01 (m, 4H) 2.72 (s, 3H) 3.07 (dd, J=16.55, 10.48 Hz, 1H) 3.26 (dd, J=17.05, 4.93 Hz, 1H) 3.55 (dd, J=7.96, 7.20 Hz, 1H) 3.90 (s, 3H) 4.05 (dd, J=7.96, 5.94 Hz, 1H) 4.10-4.21 (m, 3H) 4.89 (dd, J=10.61, 3.79 Hz, 1H) 6.74 (d, J=8.84 Hz, 1H) 7.01 (d, J=8.08 Hz, 1H) 7.11-7.22 (m, 2H) 7.61-7.69 (m, 2H)MS (ES) [M+H] calculated for C27H32FN6O4, 523.24; found 523.50.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1.[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[CH3:36].C1C(=O)N([Br:44])C(=O)C1>CCOC(C)=O>[Br:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[CH2:36][Br:44]
Reactant: Cc1ccc(C(F)(F)F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: FC(F)(F)c1ccc(CBr)c(Br)c1

Procedure:
Solid benzoyl peroxide (1.5 g, 6.3 mmol) was added to a benzene solution (200 mL) of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (10.0 g, 41.8 mmol) and NBS (8.2 g, 46.0 mmol) and the resulting mixture was refluxed. After 16 h the resulting mixture was cooled, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:36]([O:38][C:39]([CH2:41][C:42](Cl)=[O:43])=[O:40])[CH3:37]>>[CH2:1]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:8]2[CH:9]([C:13]([O:15][CH3:16])=[O:14])[N:10]([C:42](=[O:43])[CH2:41][C:39]([O:38][CH2:36][CH3:37])=[O:40])[CH2:11][CH2:12][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Product: CCCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2

Procedure:
Methyl 2-n-butyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate and ethoxycarbonylacetyl chloride are treated in the same manner as in Example 1-(2) to give methyl 2-n-butyl-5-ethoxycarbonylacetyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:27][CH2:26][C:11]2[C:12]3[C:13]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:14][CH2:15][C:16]=3[C:17](I)=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH2:2]([O:4][C:5]([N:7]1[CH2:27][CH2:26][C:11]2[C:12]3[CH:13]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH2:14][CH2:15][C:16]=3[CH:17]=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(c1cccnc1)=CC3
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(c1cccnc1)CC3
Yield: 54.8 %

Procedure:
Into a 500 ml Parr hydrogenation bottle, the product from step (b) (0.38 mmol) dissolved in EtOH (50 ml) was added. To the argon purged bottle, 100 mg of 20% Pd(OH)2 was placed. The bottle was shaken over hydrogen (50 psi) for 6 h. The reaction mixture was filtered through celite and solvent evaporated in vacuo. The residue was dissolved in DCM and washed with saturated aqueous Na2CO3. The DCM layer was dried over Na2SO4 and solvent was evaporated in vacuo to give the crude product that was purified by silica-gel chromatography (gradient elution: 0 to 80% EtOAc in hexane) to give the sub-title compound as a yellow oil (70 mg). MS: ESI (positive): 337 (M+1).