Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1.CO.C1COCC1.C(N(CC)CC)C>CCCCCC.C(O)(C)C.C[C@@H](P(C1CCCCC1)C1CCCCC1)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe]>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[C@@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Agent: [Fe]
Agent: C[C@H]([C]1[CH][CH][CH][C]1P(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Agent: [CH]1[CH][CH][CH][CH]1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 27 %

Procedure:
Under a nitrogen atmosphere, in a glove box, [6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-1-benzofuran-3-yl]acetic acid (52 mg/mL, 0.1 mmol/mL), a solution (1:1, 0.02 mL) of methanol/THF containing triethylamine (0.007 mL/mL, 0.05 mmol/mL), a solution (1:1, 0.01 mL) of methanol/THF containing dichloro-p-cymeneruthenium (II) dimer (2.5 mg/mL, 0.004 mmol/mL) and a solution (1:1, 0.026 mL) of methanol/THF containing optically active ligand (R)-(S)JOSIPHOS (2.5 mg/mL, 0.0038 mmol/mL) were added in a glass microtube. The microtube was introduced into an autoclave and sealed, and the mixture was stirred at 50° C. for 24 hr under a hydrogen atmosphere (1 MPa). The reaction mixture was diluted with a solution (1:1, 1 mL) of normal hexane/isopropylalcohol and analyzed by high performance liquid chromatography to find the title compound (conversion ratio 27%,41% ee).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)=[CH:7][N:6]=1)=[O:4].C(OC(C1SC(C(=O)NCC2C=CC(Cl)=C(Cl)C=2)=CC=1)=O)C>>[Cl:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[Cl:20])[CH2:13][NH:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)=[O:22]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)cn1
Agent: CCOC(=O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc(C(=O)O)nc1
Yield: 82 %

Procedure:
Compound (13(a)) was treated in an analogous manner to compound (12(a)) in Example 12 to obtain 5(3,4-dichlorobenzylcarbamoyl)-pyridine-2-carboxylic acid (13(b)) as an off-white solid (82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cnc(-c2ccc(Cl)cc2)c(Cl)c1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C

Procedure:
40.0 g (0.137 mol) of 3-chloro-2-(4-chlorophenyl)-5-trifluoromethylpyridine (see above for preparation) were added in portions to 75 ml of chlorosulfonic acid while stirring and cooling in ice. After the addition was complete, the mixture was stirred at 130° C. for four hours. The cooled mixture was cautiously poured into ice-water which was then extracted three times with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. Yield: 45.0 g (84%) of a dark oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:24])=[N:5]1)([CH3:3])[CH3:2].[CH2:25]1[C@@H:29]([C:30]([NH2:32])=[O:31])[NH:28][CH2:27][C@H:26]1[F:33].Cl>>[F:33][C@@H:26]1[CH2:27][N:28]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:24])[N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:29]([C:30]([NH2:32])=[O:31])[CH2:25]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: Cc1nc(-c2cn3c(n2)-c2cnc(O)cc2OCC3)n(C(C)C)n1
Agent: Cl
Product: Cc1nc(-c2cn3c(n2)-c2cnc(N4C[C@@H](F)C[C@H]4C(N)=O)cc2OCC3)n(C(C)C)n1
Yield: 42 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol and 4-cis-fluoro-L-prolinamide hydrochloride with added TEA (2.5 eq.), were reacted and the crude product recrystallised from IMS/DCM to give 382 as a white solid (68 mg, 42%). LCMS: RT=2.58 min, [M+H]+ 441. 1H NMR 400 MHz (DMSO-d6) δ: 9.04 (1 H, s), 7.76 (1 H, s), 7.10 (1 H, s), 6.91 (1 H, s), 5.95 (1 H, s), 5.87-5.80 (1 H, m), 5.42 (1 H, s), 5.29 (1 H, s), 4.49-4.36 (5 H, m), 3.74-3.73 (2 H, m), 2.46-2.45 (1 H, m), 2.20 (3 H, s), 1.40 (6 H, dd, J=6.59, 3.37 Hz)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])[N:17]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)n1
Reactant: CC1CCCC(C)N1
Solvent: CN(C)C=O
Product: CC1CCCC(C)N1Cc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2,6-Dimethylpiperidine (0.24 mL, 1.74 mmol) was added to a solution of (6-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (250 mg, 0.87 mmol) in DMF (10 mL) followed by heating at 50° C. and the resulting mixture was stirred for 18 h. The resulting mixture was partitioned between water (10 mL) and CHCl3 (20 mL). The organic layer was washed with H3O, brine, and dried over MgSO4. Concentration in vacuo gave a pale yellow solid. MS m/z: 320.3 (M+H). Calc'd. for C18H29N3O2-319.23.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36]>>[CH2:38]([O:37][C:35]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CCOC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][CH:3]=1>[Ni].N.CO>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][NH2:12])[CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2ccc(C#N)cc12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1c[nH]c2ccc(CN)cc12
Yield: 97 %

Procedure:
Raney Nickel (wet, 1.0 g) was added to a stirred solution of 192 (220.0 mg, 1.41 mmol) in 2.0 M ammonia in MeOH (10 mL). The reaction mixture was hydrogenated under an H2 balloon at 1 atmospheric pressure at RT for 3 d. The reaction mixture was filtered through a pad of Celite® and the pad was rinsed well with MeOH and water. Volatile solvent from the filtrate was removed in vacuo. The aqueous phase from filtrate was thrice extracted with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Crystallization from DCM/heptane afforded 219.1 mg (97%) of (3-methyl-1H-indol-5-yl)methanamine (194) as a white solid: 1H NMR (400 MHz, CDCl3): δ 7.87 (br s, 1H), 7.49 (s, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.95 (s, 1H), 3.95 (s, 2H), 2.31 (s, 3H), 1.59 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331 mmol) in tetrahydrofuran (800 mL) under nitrogen at −78° C. was added drop-wise a solution of butyllithium (150 mL, 2.43 M in THF) over 30 min. The resulting solution was stirred for 2 h at −78° C. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (60 g, 301 mmol) in tetrahydrofuran (800 mL) was then added drop-wise with stirring at −78° C. over 30 min. The mixture was stirred for 1 h at −78° C., then the reaction was carefully quenched with water (350 mL). The resulting mixture was extracted with ethyl acetate (2×400 mL) and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:10) as the eluent to yield 91 g (85%) of the title compound as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:19])[C:9]([F:18])([F:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:17][C:9]([F:18])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:8]([NH2:7])[CH3:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(F)(F)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-carbamic acid tert-butyl ester (92 mg, 0.32 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (0.75 ml, 9.73 mmol) was slowly added. The reaction was stirred at room temperature for 2 h then concentrated to give (R)-2,2-difluoro-1-methyl-3-phenyl-propylamine trifluoroacetate as a light brown oil which was used without further purification
Reaction SMILES: CO[C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:19]>CO>[CH3:10][O:9][C:7]([C:6]1[NH:19][C:13]2[C:14]([C:3](=[O:4])[CH:5]=1)=[CH:15][C:16]1[C:3](=[O:4])[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[NH:18][C:17]=1[C:12]=2[Cl:11])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1cccc(N)c1Cl
Solvent: CO
Product: COC(=O)c1cc(=O)c2cc3c(=O)cc(C(=O)OC)[nH]c3c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.0 g. of dimethylacetylene dicarboxylate is added dropwise to a solution of 5.25 g. of 2-chloro-1,3-diaminobenzene in 100 ml. of methanol at room temperature. The mixture is stirred for 2 hours at room temperature and the resulting yellow solid is collected by filtration. The solid is washed with 20 to 50 ml. of methanol, dried under vacuum at 60° C., and recrystallized from acetone. The tetramethyl[2-chloro-m-phenylene-diamino]dimaleate melts at 202.5°-204.5°C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([Cl:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([OH:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([O:25][C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[Cl:17])[CH:24]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (i) and the product of example 18 step (iv).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C@H:17]3[CH2:29][CH2:28][O:27][C@H:18]3[CH2:19]O2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[NH2:30]C1C(C(OC)=O)=C2C(C3CCOC=3C=N2)=CC=1.BrC1C=C(F)C=CC=1S(Cl)(=O)=O>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH2:29][CH2:28][O:27][C:18]=3[CH:19]=[N:30]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Reactant: COC(=O)c1c(N)ccc2c3c(cnc12)OCC3
Agent: O=S(=O)(Cl)c1ccc(F)cc1Br
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c3c(cnc12)OCC3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from methyl 7-amino-1,2-dihydrofuro[2,3-c]quinoline-6-carboxylate (Intermediate 23) and 2-bromo-4-fluorobenzenesulfonyl chloride and stirring at room temperature for 3 days.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][CH:3]=1.Cl[CH2:14][CH:15]1[CH2:17][O:16]1.[OH-].[K+]>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(Cl)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(OCC2CO2)c2ccccc12

Procedure:
To a stirred mixture of 44.5 parts of 4-chloro-1-naphthalenol and 115 parts of 2-(chloromethyl)oxirane are added portionwise 17.1 parts of potassium hydroxide (exothermic reaction). When the exothermic reaction is ceased, the whole is heated to reflux and stirred at reflux temperature for 2 hours. Water is added and the whole is extracted twice with trichloromethane. The combined extracts are washed three times with water, dried and evaporated. The residue is distilled, yielding 45.3 parts of 2-[(4-chloro-1-naphthalenyloxy)-methyl]oxirane; bp. 150°-151° C. at 0.2 mm. pressure.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:26])=[C:8](C(O)=O)[NH:9][C:10]=1[CH:11]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:22])([OH:3])=[O:2].[OH-].[K+].O.Cl>C(O)CO>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:12](=[CH:11][C:10]3[NH:9][CH:8]=[C:7]([CH3:26])[C:6]=3[CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:13](=[O:22])[NH:14]2)=[CH:19][CH:18]=1
Reactant: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Cc1c[nH]c(C=C2C(=O)Nc3cc(Cl)ccc32)c1CCC(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
4-(2-carboxyethyl)-3-methyl-5-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid (240 mg) suspended in ethylene glycol (5 mL) was held in a sealed tube in a pre-heated oil bath at 200° C. for 2 hours. The reaction mixture was cooled to 90° C. and potassium hydroxide (2 pellets) was added. It was then stirred at 90° C. for 30 minutes. The reaction mixture was cooled, poured into water, and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and purified on a silica gel column using ethyl acetate:hexanes:glacial acetic acid 50:50:10 as eluent to give 45 mg (21%) of 3-[2-(6-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4-methyl-1H-pyrrol-3-yl]-propionic acid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Na].[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]([CH2:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=1[O:40][CH3:41])[CH2:23][CH2:24][CH2:25][C:26](O)=[O:27].Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:22]1[CH2:29][N:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[O:40][CH3:41])[C:26](=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc(CNCC(CCCC(=O)O)c2cccc(F)c2F)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CN2CC(c3cccc(F)c3F)CCCC2=O)c(OC)c1
Reaction time: 2 h
Yield: 72.7 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.65 g, 19.1 mmol) was added to a solution of the sodium salt of 5-(2,3-difluorophenyl)-6-[(2,4-dimethoxybenzyl)amino]hexanoic acid (8.58 g, 17.3 mmol) in acetonitrile (346 mL). After 2 h, hydrochloric acid (4.0 M in dioxane; 13.0 mL; 52.0 mmol) was added. After 16 h, additional N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.24 g, 16.9 mmol), 1-hydroxybenzotriazole hydrate (1.0 g, 6.53 mmol) and triethylamine (4.83 mL, 34.6 mmol) were added. After 16 h, the reaction mixture was concentrated. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→96% dichloromethane/methanol) gave the title compound (4.72 g). MS 376.1 (M+1).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=O)=O.O>ClCCl>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cn1nccc1[C@H]1C[C@@H](O)CC[C@@H]1OC(=O)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1nccc1[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl benzoate (293 mg, 0.976 mmol) prepared in Example 162d and 2,6-lutidine (0.136 mL, 1.17 mmol) in dichloromethane (5.0 mL), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.269 mL, 1.17 mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water (10 mL) was added, followed by extraction with dichloromethane (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (367 mg, 91%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([O:22]C)=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH2:7][C:6]=2[CH:35]=1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:12]3=[C:13]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][C:19]=4[N:11]3[CH2:10][CH2:9][N:8]([CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])[CH2:7][C:6]=2[CH:35]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(CCN(C)C)Cc1cc(Cl)ccc1-3
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCN1CCn2c(c(C3CCCCC3)c3ccc(C(=O)O)cc32)-c2ccc(Cl)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 21 %

Procedure:
Methyl 3-chloro-14-cyclohexyl-6-[2-(dimethylamino)ethyl]-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 7) was dissolved in a solution THF: MeOH (1:1) (0.02 M) and to that solution 7 eq of an aqueous solution of NaOH (1N) were added. The solution was stirred at 60° C. for 3 h. The solvent was evaporated in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (21%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][N:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:21]/[CH:22]=[O:23])=[CH:3][N:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cncc2ccccc12
Product: O=C/C=C/c1cncc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-isoquinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:2]([CH:7]=1)[NH2:1]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(F)ccc1SCc1cccc([N+](=O)[O-])c1
Yield: 63.1 %

Procedure:
Following General Procedure A, the title compound (460 mg, 97%) was prepared from 2-amino-4-fluorobenzenethiol (562 g, 3.93 mmol), 1-(bromomethyl)-3-nitrobenzene (566 mg, 2.62 mmol), K2CO3 (1.8 g, 13.10 mmol) in DMF (10 ml).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][C:13](O)=[O:14])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CCOCC(=O)O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CSc1ccc(CCOCCO)cc1
Yield: 54 %

Procedure:
The 2-(4-methylthiophenyl)ethoxyacetic acid obtained according to the preceding paragraph was reduced with lithium aluminum hydride in a manner analogous to that described in Example 1(b) to give 1.97 g (54%) of 2-[2-(4-methylthiophenyl)ethoxy]ethanol in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]([CH3:23])[CH:13]=3)[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:6]2=[N:7][CH:8]=1)[NH2:2].C(Cl)Cl.[CH:35](=O)[CH3:36].N>[Cu](Cl)Cl.CCOC(C)=O.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:23])[CH:13]=[C:12]2[C:10]1[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:6]2[N:7]=[CH:8][C:3]3[N:4]([C:35]([CH3:36])=[N:2][N:1]=3)[C:5]=2[CH:11]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(NN)cnc3n1COCC[Si](C)(C)C)cn2C
Reactant: CC=O
Agent: Cl[Cu]Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4nnc(C)n43)n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
To a round bottom flask were added 2-hydrazinyl-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.181 g, 0.413 mmol), DCM (5 mL) and acetaldehyde (10.0 M in DCM, 0.206 mL, 2.06 mmol). The reaction mixture was stirred at room temperature for about 1 h. The reaction mixture was concentrated under reduced pressure followed by the addition of DMF (8 mL) and copper(II) chloride (0.107 g, 0.796 mmol). The reaction mixture was heated to about 90° C. for about 15 min. The reaction mixture was cooled to room temperature and 10% aqueous ammonia (4.5 mL) and EtOAc (6 mL) were added. The reaction mixture was heated to about 40° C. for about 30 min. The reaction mixture was cooled to ambient temperature and extracted with EtOAc (50 mL). The organic layer was washed with water (50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-100% EtOAc in heptane to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazine (0.040 g, 21%): LC/MS (Table 1, Method d) Rt=1.67 min; MS m/z: 463 (M+H)+.