Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[C:17]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=CC=CC=2)=C(S([O-])(=O)=O)C=C[C:21]=1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH:16]([C:17]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:35]=1)[CH2:21][CH2:22][NH:39][CH:36]([CH3:38])[CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Reactant: CC(C)N
Solvent: CC#N
Product: Cc1ccc(OCc2ccccc2)c(C(CCNC(C)C)c2ccccc2)c1
Temperature: 37.5 °C
Reaction time: 12 h

Procedure:
A mixture of 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (40 g), isopropylamine (20 ml), and acetonitrile (200 ml) was stirred at 35-40° C. for 12 hours. The reaction mass was distilled completely, and the obtained residue was crystallized from ethyl acetate (280 ml) to give 28 g of the title compound as a white crystalline powder. Melting point: 137-139° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1.N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].Cl>O>[C:25]([NH:1][C:2]1[O:3][CH:4]([CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH3:9])[C:5](=[O:7])[N:6]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(c1c[nH]c2ccccc12)C1OC(N)=NC1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1=NC(=O)C(C(C)c2c[nH]c3ccccc23)O1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-amino-5-[1-(indol-3-yl)ethyl]-2-oxazolin-4-one (100 mg) was dissolved into pyridine (0.5 ml). Acetic anhydride (117 μl) was added. The mixture was stirred for 2 hours at 80° C. To the reaction mixture was added water. The mixture was made acidic using 4N hydrochloric acid. The whole was extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. Concentration of the solution gave a residue, which was subjected to the silica gel chromatography. The eluent with hexane-acetone (1:1) was collected and concentrated to provide the titled compound (16 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=[C:11]([N+:12]([O-])=O)[C:6]=2[N:5]=[CH:4]1)[CH3:2]>CO.O.[Pd]>[NH2:12][C:11]1[C:6]2[N:5]=[CH:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH:8]=[C:9]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=1
Reactant: CCn1cnc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCn1cnc2c(N)cc(C(=O)OC)cc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
To a solution of methyl 1-ethyl-4-nitro-1H-benzimidazole-6-carboxylate (D206) (700 mg, 2.81 mmol, 1 equiv) in MeOH (50 ml) and H2O (5 ml) was added 10% palladium on charcoal (50% wet, 400 mg, 28% w/w) and NH4COOH (1.77 g, 28.1 mmol, 10 equiv) and the resulting mixture was stirred at 70° C. for 30 min then cooled to room temperature. The catalyst was filtered off through a pad of celite and most of the MeOH was removed in vacuo. The residue was diluted with AcOEt and the organic layer was washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give methyl 4-amino-1-ethyl-1H-benzimidazole-6-carboxylate (D207) (500 mg, 81%) as a white solid which was used in the next step without further purification. [M+H]+=220.2, RT=2.17 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 51.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 144 mg, 0.52 mmol) in THF. 137 mg (52%) of 97 was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][NH:4][CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[CH3:2].[C:30](ON1C(=O)C2C=CC=CC=2N=N1)(=[O:33])[CH2:31][CH3:32].C(O)(=O)CC>>[CH2:1]([O:3][N:4]([CH2:5][C:6]1[C:7]([F:29])=[C:8]([F:28])[C:9]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:10]([CH:18]=1)[C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:30](=[O:33])[CH2:31][CH3:32])[CH3:2]
Reactant: CCC(=O)On1nnc2ccccc2c1=O
Reactant: CCONCc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CCC(=O)O
Product: CCON(Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F)C(=O)CC
Yield: 61 %

Procedure:
The title compound was prepared by a procedure similar to that in Example 41. Namely, 5-(ethoxyamino-methyl)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide obtained in Example 17 was reacted with 4-oxo-4H-benzo[d][1,2,3]triazin-3-yl propionate prepared from propionic acid to give 5-[(ethoxy-propionyl-amino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (17.0 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](F)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1.[C:24]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)(=[O:26])[CH3:25].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:31][CH2:32][CH:28]([NH:27][C:24](=[O:26])[CH3:25])[CH2:29]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1
Reactant: CC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(-c2ccncc2F)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.22 g of 1-(3-fluoro-4-pyridyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3carboxylic acid and 0.11 g of 3-acetamidopyrrolidine are added to 12 ml of pyridine, and added with 0.13 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 24 hours, and then concentrated under a reduced pressure to remove the solvent completely. The residue is added with 20 ml of acetone and stirred at room temperature for 1 hour to obtain a product, which is then filtered and dried and used in the next reaction. (next reaction: Example 5)
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([N:16]1[C:20]([C:21](SC)=[O:22])=[C:19]([CH:25]=O)[N:18]=[C:17]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]#[C:14][CH3:15].[CH2:40]([O:47][C:48]([NH:50][CH:51](P(OC)(OC)=O)[C:52]([O:54][CH3:55])=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH3:55][O:54][C:52]([C:51]1[N:50]([C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:21](=[O:22])[C:20]2[N:16]([CH2:12][C:13]#[C:14][CH3:15])[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:29][CH2:28]3)=[N:18][C:19]=2[CH:25]=1)=[O:53]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)SC
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(C(=O)OC)n(C(=O)OCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.079 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then 5 ml of dichloromethane containing 0.194 g of t-butyl 4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate were added to a 2 ml dichloromethane solution of 0.174 g of methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=O)C.[CH3:27][NH2:28]>C(O)CCC>[CH3:27][NH:28][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH3:20])[C:12]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)CCCCCc1c(-c2cccnc2)n(C)c2ccccc12
Solvent: CCCCO
Product: CNC(=O)CCCCCc1c(-c2cccnc2)n(C)c2ccccc12

Procedure:
A solution of 4 g of 3-(5-ethoxycarbonylpentyl)-1-methyl-2-(3-pyridyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized from ethyl-ether to yield the 3-[5-(N-methylcarbamoyl)pentyl]-1-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][N:23]1[CH2:24][CH2:25][C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: O=C(NCCBr)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCC(c2ccccc2)(c2ccccc2)C1)OCc1ccccc1
Reaction time: 15 h

Procedure:
(2-Bromo-ethyl)-carbamic acid benzyl ester (1.10 g, 4.26 mmol), 3,3-diphenyl-pyrrolidine (Example A18, 836 mg, 3.75 mmol) and DIPEA (1.0 mL 5.7 mmol) are dissolved in THF (20 mL) and stirred for 15 h at reflux. The mixture is quenched with Na2CO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic extracts are washed with sat. aq. Na2CO3 (30 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, EtOAc-heptane) to provide the title compound.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH3:4].C(O)(=O)C>C(O)C>[CH2:3]([C@:5]12[CH2:13][CH2:12][C@@H:11]3[C@@H:14]4[C:19]([CH2:20][CH2:21][C@H:10]3[C@@H:9]1[CH2:8][CH2:7][C@@H:6]2[OH:23])=[CH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[CH3:4]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
Add sodium borohydride (200 mg.) in ethanol (25 cc.) to 13β-ethylgon-4-en-3,17-dione (1 g.) in ethanol (50 cc.) at 8°. After 15 minutes add an excess of acetic acid and evaporate the solution to dryness under reduced pressure. Add water, collect the product in ether, and after this work up in the usual manner, recrystallize from a mixture of ether and pentane to obtain 13β-ethyl-17β-hydroxy-gon-4-en-3-one; ultraviolet absorption peak at 240 mμ (ε 15,500); infrared absorption peaks at 2.94, 6.06, 6.23.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:22]=[C:21]3[C:13]([C:14]4[C:15](B5OC(C)(C)C(C)(C)O5)=[CH:16][CH:17]=[C:18]([C:23]([NH2:25])=[O:24])[C:19]=4[NH:20]3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Br[C:36]1[C:44]([F:45])=[C:43]2[C:39]([CH:40]=[CH:41][NH:42]2)=[CH:38][CH:37]=1.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>[F:45][C:44]1[C:36]([C:15]2[C:14]3[C:13]4[C:21](=[CH:22][C:10]([C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[O:9])=[CH:11][CH:12]=4)[NH:20][C:19]=3[C:18]([C:23]([NH2:25])=[O:24])=[CH:17][CH:16]=2)=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2
Reactant: Fc1c(Br)ccc2cc[nH]c12
Reactant: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(B4OC(C)(C)C(C)(C)O4)c23)CC1
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: Cc1ccccc1
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(-c4ccc5cc[nH]c5c4F)c23)CC1
Temperature: 90 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of 7-(4-methylpiperazine-1-carbonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole-1-carboxamide (prepared according to the procedure of Step 1 of Example 2-1, 75 mg, 0.065 mmol), 6-bromo-7-fluoro-1H-indole (prepared according to U.S. pat. appl. 2007/112005, 18.7 mg, 0.087 mmol), and 2 M aqueous sodium carbonate (0.081 mL, 0.162 mmol) in toluene (0.8 mL) and ethanol (0.2 mL) was purged with argon, treated with tetrakis(triphenylphosphine)palladium (7.5 mg, 0.007 mmol) and heated at 90° C. After 16 h, the mixture was cooled to rt. The residue was purified by preparative HPLC. The resulting TFA salt was partitioned between NaHCO3 (aq) and EtOAc, and the organic extracts were dried and concentrated to provide 4-(7-fluoro-1H-indol-6-yl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as an off-white solid (9 mg, 30%). 1H NMR (400 MHz, methanol-d4) δ 7.99 (d, J=7.5 Hz, 1H) 7.68 (d, J=0.9 Hz, 1H) 7.52 (d, J=7.9 Hz, 1H) 7.39 (d, J=3.5 Hz, 1H) 7.25 (dd, J=8.1, 1.1 Hz, 1H) 7.21 (d, J=7.5 Hz, 1H) 7.08 (dd, J=8.1, 6.4 Hz, 1H) 6.92 (dd, J=8.1, 1.5 Hz, 1H) 6.63 (t, J=3.3 Hz, 1H) 3.77 (br. s., 2H) 3.49 (br. s., 2H) 2.51 (br. s., 2H) 2.39 (br. s., 2H) 2.30 (s, 3H). Mass spectrum m/z 470.1 (M+H)+.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/C(C1C(C)(C)CC=CC=1C)=O.CC1OC=CC(=O)C=1O.[CH3:24][CH2:25][C:26]1O[CH:31]=[CH:30][C:28](=O)[C:27]=1O>>[CH3:24][C:25]1[CH2:26][CH2:27][CH:28]([C:2]([CH3:3])=[CH2:1])[CH2:30][CH:31]=1
Reactant: CCc1occc(=O)c1O
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Agent: Cc1occc(=O)c1O
Product: C=C(C)C1CC=C(C)CC1

Procedure:
Beta-damascenone (having the structure: ##STR13## Maltol; Ethyl maltol;
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[NH2:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[CH:1]1([C:4]([NH:15][CH:16]([CH2:22][SH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarbonyl chloride (3.1 mL) was added to a suspension of triethylamine (4.68 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5.2 g) in DCM (200 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with ethanol and the solvent evaporated. The residue was suspend in ethyl acetate (200 mL) and washed with saturated sodium bicarbonate solution (2×150 mL), aqueous HCl solution (2M, 2×150 mL) and brine (150 mL), then dried over magnesium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 isohexane:ethyl acetate to give the subtitled compound as a white solid. Yield 5 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][C:21](O)=[O:22])=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(NC(NC2CCCCC2)=O)CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH:9][C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]=[CH:11][CH:12]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O=C(Cc1ccc2ncccc2c1)NNc1ccc(Cl)nn1

Procedure:
To a suspension of 3-chloro-6-hydrazinylpyridazine (3 g, 20.75 mmol) and 2-(quinolin-6-yl)acetic acid (4.27 g, 22.83 mmol) in DCM (200 mL) was added DCC (5.14 g, 24.90 mmol). The solution was stirred at it over weekend. The title compound as a white solid containing some dicyclohexyl urea was collected and used in the next step without further purification (8 g, 100%). LCMS (method A): [MH]+=314.1, tR=2.851 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[C:31]([O:37][CH3:38])=[CH:30][C:29]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[C:31]([O:37][CH3:38])=[CH:30][C:29]=1[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
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: [K+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 79.8 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (from Step 1 of Example 73, 500 mg, 1.220 mmol), (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (Intermediate SSSS; 479 mg, 1.709 mmol) potassium carbonate (506 mg, 3.66 mmol), and Pd(Ph3P)4 (141 mg, 0.122 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (4576 μl) and water (1525 μl) were added. The flask was fitted with a reflux condenser and heated in a 50° C. heating bath for 40 min. The mixture was partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptane) to give perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (593.7 mg, 0.973 mmol, 80% yield) as a white foam. m/z (ESI) 609.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]2[CH:21]=[CH:20][C:19](F)=[C:18](F)[CH:17]=2)=[N:6][CH:7]=1.Cl.[C:25]([O:29]C(N1CCCC(C2C=CC(OC)=CC=2)C1)=O)(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]2[CH:21]=[CH:20][C:19]([O:29][CH3:25])=[CH:18][CH:17]=2)=[N:6][CH:7]=1
Reactant: Fc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1F
Reactant: COc1ccc(C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Product: COc1ccc(C2CNCCC2COc2ccc(Cl)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis of 5-Chloro-2-[(3SR,4SR)-3-(3,4-difluoro-phenyl)-piperidin-4-ylmethoxy]-pyridine; hydrochloride the title compound was prepared from 445-Chloro-pyridin-2-yloxymethyl)-3-(4-methoxy-phenyl)-piperidine-1-carboxylic acid tert-butyl ester as off-white foam (1:1 mixture cis:trans). MS (m/e): 333.4 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:12][C@H:11](O)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH:37]1[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]1>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:37]4[CH2:42][CH2:41][CH:40]([CH2:43][OH:44])[CH2:39][CH2:38]4)[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: ClCCl
Product: OCC1CCN([C@H]2C[C@H](c3nc4ccc(Br)cc4s3)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 1D (0.177 mmole) was dissolved in anhydrous dichloromethane (2 ml). Potassium carbonate (50 mg, 0.362 mmole) was added followed by trifluoromethanesulfonic anhydride (40 μl, 0.238 mmole). The mixture was allowed to stir at room temperature for 2 hours, then another portion of potassium carbonate (100 mg, 0.724 mmole) was added, followed by 4-piperidinemethanol (61 mg, 0.530 mmole). The resulting mixture was stirred at room temperature overnight. It was then quenched with water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (0.3% ammonium hydroxide and 3% methanol in dichloromethane) to give 29 mg (43%) of title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.83 (d, J=8.54 Hz, 1H) 7.56 (dd, J=8.54, 1.83 Hz, 1H) 3.74-3.86 (m, 1H) 3.52 (d, J=6.10 Hz, 2H) 3.08-3.19 (m, 1H) 2.95 (d, J=10.68 Hz, 2H) 2.51-2.62 (m, 4H) 1.79 (d, J=10.68 Hz, 4H) 1.48-1.59 (m, 2H) 1.25-1.38 (m, 2H). MS: (M+H)+=381/383.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.C(P(CCCC)CCCC)CCC.[O:36]=[S:37]1(=[O:47])[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]O)[CH2:39][CH2:38]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:45][CH2:44][CH2:43][N:40]4[CH2:39][CH2:38][S:37](=[O:47])(=[O:36])[CH2:42][CH2:41]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
4-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (5.0 g, 15.6 mmol) was suspended in dichloromethane (150 ml) and tributylphosphine (11.1 ml, 44.6 mmol) was added followed by stirring at ambient temperature for 30 minutes. To this mixture was added 3-(1,1-dioxothiomorpholino)-1-propanol (4.2 g, 21.8 mmol) followed by the addition of 1,1′-(azodicarbonyl)dipiperidine (11.7 g, 46.4 mmol) in portions. The mixture was stirred at ambient temperature overnight then diluted with ether (300 ml) and the precipitate was removed by filtration. The residue was chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give a solid which was triturated with ethyl acetate filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (5.4 g, 70%).