Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A followed by either B or C, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].CO[CH2:13][Cl:14].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH2:13][Cl:14])=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(F)cc1Cl
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(CCl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
17.6 g (0.11 mol) of 2-chloro-4-fluoroanisole was dissolved in a dichloromethane solution of 1N titanium tetrachloride, and 88.3 g (1.10 mol) of methoxymethyl chloride was dropwise added thereto at room temperature, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into water, followed by stirring at room temperature for 2 hours, and then the aqueous phase was removed The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, the obtained residue was purified by silica gel column chromatography to obtain 15.5 g (yield: 68%) of the desired product.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[NH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1>O1CCCC1>[C:1]1(=[O:5])[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[C:2]1=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc2c(c1)CCCN2
Solvent: C1CCOC1
Product: O=C1C(=O)N2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the refluxing mixture of oxalyl chloride (22 ml) in dry tetrahydrofuran (THF, 100 ml) was added 1,2,3,4-tetrahydroquinoline (18.5 g) in dry THF (150 ml) dropwise. The mixture was refluxed for 3.5 hours after addition was completed, then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in carbon disulfide (800 ml) and heated up to reflux. To the refluxing mixture was added aluminum chloride (35 g) portionwise over 5 hours period under stirring. The reaction mixture was refluxed for an additional 3 hours and allowed to stand for overnight at room temperature. After decantation of the solvent, the residue, cooled by an ice bath, was treated with water (150 ml). The mixture was extracted with chloroform and washed with water and dried over anhydrous sodium sulfate. Evaporation of chloroform afforded the title compound. The compound was recrystallized from ethanol to give 21 g (80%) of dark red needles, mp 198°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25]([OH:27])=O)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:27][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:9])[F:11]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Reactant: N=C(NO)c1ccc(N)nc1
Product: Nc1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)c(Cl)c5)nc34)n2)cn1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) (205 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (90 mg, 34%). MS (ISP) 526.1 [(M+H)+]; mp 234° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cccc(Br)c1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Br)c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-bromobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-bromophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:6]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=[CH2:31])[CH2:2]C=C>C(Cl)Cl.C1(C2C3C=CC(C(O)=O)=CC=3N3CCN(C)CC4C=C(OC)C=CC=4C=23)CCCCC1>[CH:18]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:13]=3[N:5]3[CH2:1][CH2:2][CH:31]=[CH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:6]=23)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C=CCCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCC=Cc1ccccc1-3
Yield: 68 %

Procedure:
Methyl 1-but-3-en-1-yl-3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate was dissolved in DCM (0.02M) and treated with Zhan catalyst 1 (0.3 eq) at 35° C. for 1 h. After evaporation of solvent in vacuo the residue was purified by chromatography (PE/EtOAc 9:1) to afford the title compound (68%); MS (ES+) m/z 386 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.O.[Cu]>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(I)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2ccc3ccccc32)cc1
Temperature: 150 °C
Yield: 79.1 %

Procedure:
A mixture of 1-H-indole (58.5 mg, 0.500 mmol), 1-(iodo)-4-methylbenzene (0.218 g, 1.00 mmol), copper powder (32.0 mg, 0.500 mmol), and K2CO3 (0.138 g, 1.00 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated at 150° C. for 12 h under argon. The resulting mixture was diluted with H2O (6 mL). The aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine 10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by preparative TLC using EtOAc/hexane (1:4) to give the desired product (82 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.67 (d, 1H, J=7.7 Hz), 7.52 (d, 1H, J=7.4 Hz), 7.38 (d, 2H, J=8.4 Hz), 7.34-7.29 (m, 3H), 7.21 (t, 1H, J=7.0 Hz), 7.15 (t, 1H, J=7.0 Hz), 6.66 (d, 1H, 3.3 Hz), 2.43 (s, 3H); ESMS m/e: 208.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].N1C(C)=CC=CC=1C.CN1CCCC1.Cl[C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:27]1[C:28]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:33][C:29]=2[N:30]=[CH:31][N:32]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CN1CCCC1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2,6-lutidine and 0.9 ml of N-methylpyrrolidine to 360 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it was returned to room temperature, water was added, the precipitated solid was filtered out and washed with water and diethyl ether, and the collected solid was dried to obtain 112 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([C@@H:53]([NH2:55])[CH3:54])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:55][C@H:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH3:54])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: C[C@H](N)c1ccccc1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@@H](C)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (S)-(−)-1-phenylethylamine (Aldrich) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:10])=[O:9])[C:5]([OH:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[F:25]>>[F:25][C:18]1[CH:19]=[C:20](/[CH:21]=[CH:10]/[C:8]([C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[OH:11])=[O:9])[CH:23]=[CH:24][C:17]=1[O:16][CH3:15]
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C=O)cc1F
Product: COc1ccc(/C=C/C(=O)c2cc(C)cc([N+](=O)[O-])c2O)cc1F
Yield: 75.2 %

Procedure:
2-Hydroxy-5-methyl-3-nitroacetophenone (100 mg, 0.51 mmol) and 4-methoxy-3-fluorobenzaldehyde (95 mg, 0.61 mmol) were reacted according to the same procedure as Preparation 22 to give 127 mg (Yield 74%) of the title compound.
Reaction SMILES: [C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([N+:22]([O-])=O)[CH:16]=2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][CH2:8][N:9]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([NH2:22])[CH:16]=2)=[N:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2cc(C)n(CCO[Si](C)(C)C(C)(C)C)n2)cc1N
Reaction time: 5 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (867 mg) was dissolved in ethanol and Palladium (10%) on activated carbon was added. The mixture was subject to barometric hydrogenation under balloon pressure for five hours at room temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure to give crude 5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine as a white solid, which was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[O:21][CH2:20]3)=[CH:13][CH:12]=2)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]([CH3:26])[N:7]([CH3:27])[C:6]=1[CH3:28])=[O:4].[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:15][CH:16]=2)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]([CH3:26])[N:7]([CH3:27])[C:6]=1[CH3:28])=[O:4]
Reactant: CC(C)N
Reactant: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccc(OCC2CO2)cc1
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccc(OCC(O)CNC(C)C)cc1
Yield: 90 %

Procedure:
Eleven grams of 1,2,6-trimethyl-4-[4-(2,3-epoxypropoxy)-phenyl]-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (melting point 126°), 3 g of isopropylamine and 40 ml of alcohol are heated at reflux overnight, concentrated in vacuo and treated with acetone. The product precipitates as the hydrochloride salt, white crystals of melting point 211°-212°C, in a yield of 90% of theory.
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH2:22]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([F:21])[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:24])[CH3:23]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(F)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Yield: 77.4 %

Procedure:
Twenty percent Pd/C was added to a solution of 3-benzyloxy-1-ethyl-6,7-difluoro-1H-quinazoline-2,4-dione (Example C, 0.055 g, 0.16 mmol) in 25 mL of THF and 25 mL of methanol. This was shaken under 50 PSI of hydrogen for 12.5 hours. The mixture was filtered and concentrated to afford 0.03 g of the title compound as a solid, mp 172-174° C.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:25][CH2:24]1>N1C=CC=CC=1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[C:6]([NH:7][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:12])=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:34])[C:30]([F:33])([F:31])[F:32])[CH2:25][CH2:24]3)[CH:15]=2)(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(OC(F)F)c2)cc1N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
0.429 g of 3-(difluoromethoxy)-aniline (2.7 mmol) were dissolved in 5 mL of pyridine. 1 g of 4-methyl-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonylchloride (2.7 mmol) were added slowly at room temperature. After stirring for 16 h at room temperature, the reaction mixture was evaporated several times after addition of toluene. The residue was dissolved in dichloromethane and washed several times with 5% aqueous ammonium chloride. The organic phase was then washed with saturated aqueous sodium chloride, dried over sodium sulphate, filtered, and the solvent evaporated. The crude product was purified via silica gel chromatography using dichloromethane/methanol (0-5%) to yield 0.63 g of product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][CH2:12][C@H:13]([NH:20]C(=O)OC(C)(C)C)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:4]=2[NH:3]1.[ClH:28]>C1COCC1>[ClH:28].[NH2:20][C@H:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:1])[NH:3][C:4]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Temperature: 25 °C

Procedure:
tert-Butyl {(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}carbamate (Intermediate 7) (67 mg, 0.18 mmol) was placed in a 10-mL RBF under a nitrogen atmosphere and dissolved in THF (2 mL). HCl (1 mL, 4.0 mmol) (4M in 1,4-dioxane) was added, and the reaction was stirred at room temperature for sixteen hours. The reaction then concentrated in vacuo, with repeated cycles of dilution/concentration with THF to minimize the residual HCl, to afford 5-[(2R)-2-amino-2-phenylethoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride as a yellow solid. LRMS (ESI) calc'd for (C15H16N3O2) [M+H]+, 270.1. found 270.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].O[C:13]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([O:5][C:13]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ccsc12
Reactant: O[C@@H](CCCl)c1ccccc1
Solvent: C1CCOC1
Product: ClCC[C@@H](Oc1cccc2ccsc12)c1ccccc1
Reaction time: 18 h
Yield: 42.6 %

Procedure:
4,4-(Dimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-triphenyl phosphonium (1.15 g, 2.80 mmol) was added in one portion to a stirred solution of (S)-(−)-3-chloro-1-phenyl-1-propanol (317 mg, 1.86 mmol) and 7-hydroxybenzo[b]thiophene (280 mg, 1.86 mmol) in dry THF (5 mL) under an inert atmosphere on nitrogen. The resulting suspension was allowed to stir for a further 18 hrs before the solvent was removed in vacuo. The residue was triturated with hexane (ca. 15 mL) and the solid filtered, the filtrate was concentrated in vacuo and the resulting pale yellow oil was purified by flash chromatography eluting silica gel with hexane:ether [95:5] to yield the title compound as a colourless oil (240 mg, 43%); Rf=0.78 in hexane:ether [10:1]; δH (300 MHz, CDCl3) 7.66–7.00 (9H, m, Ar); 6.55 (1H, d, Ar), 5.80–5.72 (1H, m, CHO), 3.91–3.60 (2H, m, CH2), 2.62–2.50 (1H, m, CHH), 2.38–2.22 (1H, m, CHH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](OC(C)(C)C)=O.ClC1[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:24]=1[C:25]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:26]>>[Cl:45][C:42]1[CH:43]=[N:44][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:7]2[CH2:6][O:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=2)=[C:24]([CH:41]=1)[C:25]([NH:27][C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:26]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(F)c1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC[C@@H]3COc3cccc(F)c3)CC2)cc1
Yield: 90.3 %

Procedure:
The title compound (D201) (80 mg) was prepared according to the experimental procedure described in Description 160 starting from (R)-tert-butyl 2-((3-fluorophenoxy)methyl)pyrrolidine-1-carboxylate (D42) (100 mg, 0.338 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (61.8 mg, 0.169 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:20])([CH3:1])[CH3:21])=[N:6]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNCCCC
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid from the Step E above in 1 mL DMF was added 23.0 mg HOBt, 19.4 mg dibutylamine, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 65˜100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.33 min. (m/Z=402.3, 424.3).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH3:17]>O1CCOCC1>[N:1]1([C:7]2[N:12]=[CH:11][C:10]([S:13]([NH2:17])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (1.25 g, 4.8 mmol) was dissolved in a 0.5M solution of ammonia in dioxane (20 mL) and the mixture stirred for 16 hours at room temperature. The mixture was filtered and concentrated in vacuo to afford 6-morpholin-4-yl-pyridine-3-sulfonic acid amide as a white solid 1.1 g (96% yield).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:1])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bromide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl ether ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.