Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH:38]C=O)[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]>CO>[CH2:2]([O:4][N:5]=[C:6]([C:33]1[N:34]=[C:35]([NH2:38])[S:36][CH:37]=1)[C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:28]([OH:30])=[O:29])=[C:14]([CH2:17][S:18][C:19]3[N:23]([CH2:24][C:25]([OH:27])=[O:26])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH3:3]
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CC(=O)O)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 64.1 %

Procedure:
Conc. hydrochloric acid (0.54 g.) was added dropwise at ambient temperature to a suspension of 7-[2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g.) in methanol (70 ml.), and the resulting mixture was stirred for 4.5 hours at ambient temperature. The solvent was distilled off under reduced pressure and water (30 ml.) was added to the residue. The mixture was adjusted to pH 7.2 with a saturated aqueous solution of sodium bicarbonate, and an insoluble material was filtered off. The filtrate was washed with ethyl acetate (25 ml.) and then in turn adjusted to pH5.5, 4.5 and 3.8, and in turn washed with ethyl acetate at each pH. The aqueous layer was adjusted to pH1.7, and precipitate were collected by filtration, washed with water (200 ml.) and dried under reduced pressure to give 7-[2-ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetamido]-3-(1-carboxymethyl-1H-tetrazol- 5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.65 g.).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[F:23][C:24]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:25]=1[NH2:26].O>C(O)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:26][C:25]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:24]=1[F:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
35.3 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-ethoxyacrylate are dissolved in 120 ml of ethanol, and 12.9 g of 2,4-difluoroaniline are added dropwise, while cooling with ice. The mixture is stirred at room temperature for 1.5 hours, 120 ml of water are added, while cooling, and the precipitate is filtered off with suction, rinsed with ethanol/H2O (1:1) and dried. 40.5 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)acrylate are obtained, melting point: 84°-86° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].C(Cl)(Cl)Cl.[CH3:14][NH:15][S:16]([C:19]1[CH:20]=[C:21]([C:29](Cl)=[O:30])[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=1)(=[O:18])=[O:17]>C(Cl)(Cl)Cl.O>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:29]([C:21]1[C:22]2[O:27][CH2:26][CH2:25][O:24][C:23]=2[CH:28]=[C:19]([S:16](=[O:18])(=[O:17])[NH:15][CH3:14])[CH:20]=1)=[O:30])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 66.1 %

Procedure:
82 g of dextrorotatory 1-ethyl-2-aminomethylpyrrolidine, 600 ccm of chloroform and, gradually, at a temperature of from 5°-10° C, 200 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were introduced into a balloon flask with an agitator and a thermometer. After the addition of a liter of water chloroform was distilled and then the remaining solution was filtered. The base was precipitated by the addition of 60 cm3 of 20% ammonia. The crystals formed were dried off, washed with water and then dried. 162 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 136°-137° C.; yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1F.[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]#[CH:15])=[CH:17]1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: C#Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c2ccccc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (4.79 g) in dimethylformamide (25 ml) was added 3-ethynylindole (2.9 g) and potassium carbonate (2.84 g), the mixture was heated at 90° C. for 3 hours under an atmosphere of nitrogen and then left to stir overnight at room temperature. The reaction was diluted with water (100 ml) and extracted with hexane (2×100 ml). The organic fractions were separated, combined, evaporated to dryness and purified by column chromatography on silica gel (300 g) eluted with hexane:ethylacetate (97:3) to give the title compound as a white solid (1.3 g), m.p. 120-122° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[Cl:20])[CH2:32][CH2:31]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2Cl)CC1
Yield: 66 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 66%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.49 (m, 3H), 3.10-3.15 (m, 4H), 3.81 (s, 3H), 3.08-4.12 (m, 4H), 7.00-7.12 (m, 3H), 7.24-7.40 (m, 3H), 7.49-7.65 (m, 2H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:2]1([O:1][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:18][C@@H:19]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][OH:21])=[O:13])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1COc1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1COc1ccccc1
Yield: 84 %

Procedure:
2 g (8.8 mmol) of 2-phenoxymethylbenzoic acid were reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 7a. 2.7 g (84%) of the product were obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].CS(O[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1)(=O)=O>CN(C)C=O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([CH2:11][S:5][CH2:3][CH3:4])[CH:17]=1
Reactant: CS(=O)(=O)OCc1cncc(Br)c1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of sodium hydride (60% dispersion in mineral oil, 0.094 g, 2.35 mmol) in N,N-dimethylformamide (9.4 mL) was added ethanethiol (0.140 mL, 1.88 mmol). The reaction was warmed to room temperature and stirred for 30 minutes. It was then cooled to 0° C., and a solution of the title compound from Example 62 Step A (0.250 g, 0.939 mmol) in N,N-dimethylformamide (1 mL) added. The resulting solution stirred at room temperature until the reaction was complete. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 233.91 [M+2+H]+; 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H), 8.39 (s, 1H), 7.79 (s, 1H), 3.62 (s, 2H), 2.39 (q, J=7.4, 2H), 1.19 (t, J=7.4, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[NH2:15][C@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1)=[O:18]>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C@@H:16]([NH:15][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:17]([N:19]2[CH2:20][CH2:21][CH:22]([OH:25])[CH2:23][CH2:24]2)=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared according to EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(R)-amino-3-(4-fluorophenyl)-1-(4-hydroxypiperidin-1-yl) propan-1-one hydrochloride (Preparation 84). Purification by chromatography using dichloromethane/methanol (92:8) as the eluent gave the title compound as a pale yellow powder. m/z (ES+)=445.34 [M+H]+; RT=3.10 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C(Cl)Cl>[C:38]([NH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)(=[O:40])[CH3:39]
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A solution of N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (61 mg, 0.14 mmol) in CH2Cl2 (3 mL) was treated with pyridine (0.058 mL, 0.72 mmol) and acetic anhydride (0.13 mL, 1.4 mmol). The resultant mixture was stirred at RT for 2 days. The reaction was quenched with saturated aqueous NaHCO3 and was further stirred for 2 h. The mixture was diluted with EtOAc (30 mL) and was washed with saturated aqueous NaHCO3 (20 mL), water (20 mL) and brine (20 mL). The mixture was concentrated in vacuo and purified by silica gel chromatography to provide N-(4-(2-acetamidopyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (46 mg, 69% yield). 1H NMR (400 MHz, DMSO-d6): δ10.56 (s, 1H), 10.54 (s, 1H), 9.96 (s, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.92 (t, 1H), 7.65 (d, J=1.9 Hz, 1H) 7.59 (m, 2H), 7.24 (dd, J=11.2, 2.5 Hz, 1H), 7.15 (m, 2H), 7.01 (m, 1H), 6.68 (dd, J=5.7, 2.3 Hz, 1H), 2.02 (s, 3H), 1.60-1.52 (m, 4H); MS (ESI) m/z: 467.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[H-].[Na+].I[CH2:39][C:40]#[N:41]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:39][C:40]#[N:41])[CH2:28][CH2:29]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: N#CCI
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(CC#N)CC2)CC1c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 66.1 %

Procedure:
To a solution of 4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide (216 mg, 0.382 mmol) in DMF (1 mL) was added sodium hydride (55% dispersion in mineral oil, 6 mg, 0.14 mmol). After stirring for 30 min at ambient temperature iodoacetonitrile (9 μl, 0.12 mmol) was added And the suspension was stirred for 18 h at this temperature. After the addition of further iodoacetonitrile (9 μl, 0.12 mmol) the resulting dark brown solution was stirred for further 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL) and was washed with aqueous sodium carbonate (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic phases were dried over sodium sulfate. Purification by chromatography (SiO2, (ethyl acetate:triethylamine=95:5):methanol=100:0 to 70:30) afforded the title compound (45 mg, 88%) as a white foam. MS m/e: 567.1 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:10]3.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>>[N:1]1([C:2]2[C:7]3[O:8][C:9]4([C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]4)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1cccc2c1OC1(CC1)C2=O
Reactant: BrCCCCBr
Product: O=C1c2cccc(N3CCCC3)c2OC12CC2
Yield: 19.1 %

Procedure:
7-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (3.5 g) and 1,4-dibromobutane (4.3 g.) were reacted in the same manner as Example 31, and the product was recrystallized from ethanol to give 7-(1-pyrrolidinyl)spiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.87 g.) as yellow needles melting at 101.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[C:6](F)=[N:7][CH:8]=1)#[N:2].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1>>[CH3:10][C:5]1[C:6]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH3:11])=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2]
Reactant: CC1CCCCN1
Reactant: Cc1cc(C#N)cnc1F
Product: Cc1cc(C#N)cnc1N1CCCCC1C
Yield: 92.7 %

Procedure:
A solution of 5-cyano-2-fluoro-3-methylpyridine (Molekula, 1.50 g; 11.02 mmol) and 2-methylpiperidine (5.20 mL; 44.08 mmol) was heated to 90° C. for 18 h. Reaction mixture was extracted with EtOAc, the organics dried over MgSO4, evaporated under vacuum to give the title compound as a brown oil (2.2 g, 93%). 1H NMR (DMSO-d6) δ 8.46 (d, J=2.3 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 4.01-3.96 (m, 1H), 3.37-3.25 (m, 2H), 3.17-3.09 (m, 1H), 2.22 (s, 3H), 1.72-1.46 (m, 6H), 1.11 (d, J=6.6 Hz, 3H). HPLC (Method B) Rt 3.60 min (Purity: 84.5%). LC/MS (Method A): 216.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH3:3].[OH-].[Na+]>CO.O>[CH3:15][CH:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH3:14]
Reactant: COC(=O)CCc1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cc(C(C)C)c(CCC(=O)O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
3-[2,4,6-Tris(1-methylethyl)phenyl]propionic acid, methyl ester (2.12 g, 7.3 mmol) was dissolved in 100 mL methanol and 10 mL water. Sodium hydroxide (0.32 g, 8.0 mmol) was added and the resulting solution was stirred at room temperature for 4 hours. Concentrated in vacuo and partitioned the residue between water and diethyl ether. The aqueous layer was acidified with concentrated HC1 and extracted with dichloromethane. The organic extract was dried over MgSO4, filtered, and concentrated to give 1.87 g of 3-[2,4,6-tris(1-methyl-ethyl)phenyl]propionic acid as a white solid, mp 194°-196° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([Li])=[CH:2]1.[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[N:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]([CH:12]([NH:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:10][CH:9]=1
Reactant: Clc1ccc(C=Nc2ccncc2)cc1
Reactant: [Li]c1ccoc1
Product: Clc1ccc(C(Nc2ccncc2)c2ccoc2)cc1

Procedure:
The title compound is prepared in a similar manner to Examples 5,6 and 7 from 3-furyl lithium (obtained by treating 3-iodofuran with butyl lithium) and 4-(p-chlorobenzylideneamino)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C@H:4]([OH:6])[CH3:5].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C@H:4]([O:6][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1)[CH3:5]
Reactant: C1=COCCC1
Reactant: COC(=O)[C@@H](C)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: COC(=O)[C@@H](C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-hydroxy-propionic acid methyl ester (10 g) and 3,4-dihydro-2H-pyran (15 mL) in DCM (400 mL) was added camphorsulfonic acid (50 mg) (exothermic reaction). The reaction mixture was stirred at ambient temperature for 2 hours, and washed with saturated bicarbonate solution (20 mL). The organic layer was dried, filtered and concentrated to obtain crude (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester, which was used as is in the next step. To a stirred suspension of LAH (4 g) in anhydrous ether (400 mL) at 0-5° C. was added (R)-2-(tetrahydro-pyran-2-yloxy)-propionic acid methyl ester dropwise over 30 minute period. After completion of the addition, the cold bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was cooled to 0-5° C., and ethyl acetate was added dropwise to quench excess LAH, which was followed by the addition of saturated sodium sulfate solution and solid sodium sulfate. The resulting mixture was stirred at room temperature for 1 hour, the solid was filtered off, and the solid was washed with ether. The combined organic layer was dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography using a silica gel stationary phase (pre-treated with 0.1 triethylamine in hexanes) and hexanes in ethyl acetate to get (R)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol. 1H NMR (400 MHz, CDCl3): δ 4.51-4.75 (1H, m) 3.76-4.02 (2H, m) 3.42-3.62 (3H, m) 1.67-1.90 (2H, m) 1.46-1.63 (4 h, m) 1.10-1.24 (3H, m).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:15]=[CH:14]2)[CH3:5])[CH:2]=[CH2:3].[OH-].[Na+]>CC(O)=O.C(O)(C(F)(F)F)=O>[CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[F:20])[N:16]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCCCOc1cc2ccn(-c3ccc(Cl)cc3)c2cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: C=CCN(C)CCCCOc1cc2c(cc1F)N(c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A solution of 25 mg (0.67 mol) Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-1H-indol-5-yloxy]-butyl}-methyl-amine in 1 ml AcOH/TFA (1:1) was treated at 0° C. with 70 mg (1.11 mmol) NaBCNH3 and stirred at room temperature for 8 hours. The mixture was poured into icy 2M NaOH and extracted three times with Et2O. Evaporation of the solvent, drying with MgSO4 and column chromatography on silica gel with CH2Cl2/MeOH/NEt3 10:1:0.1 gave 20 mg (80%) Allyl-{4-[1-(4-chloro-phenyl)-6-fluoro-2,3-dihydro-1H-indole-5-yloxy]-butyl}-methyl-amine, MS: 389 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3](S(C2C=CC=CC=2)(=O)=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([Mg]Br)=[C:24]([F:32])[CH:23]=1>C1COCC1>[Cl:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)=[C:24]([F:32])[CH:23]=1
Reactant: O=S(=O)(c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Reactant: COc1cc([Mg]Br)c(F)cc1Cl
Solvent: C1CCOC1
Product: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Yield: 84 %

Procedure:
3-Chloro-2-phenylsulfonyl-5-trifluoromethylpyridine was stirred with 4-chloro-2-fluoro-5-methoxyphenylmagnesium bromide for 2.5 hours at room temperature in THF. Working-up by distillation gave the coupling product 2-(4-chloro-2-fluoro-5-methoxyphenyl)-3-chloro-5-trifluoromethylpyridine in a yield of 84%, which is outstanding.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([N+:22]([O-])=[O:23])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1>CO.[Pd]>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH:22][OH:23])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: ONc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-7-nitro-quinazoline hydrochloride (2.90 g, 7.98 mmol) was dissolved in 700 mL methanol and hydrogenated with 10% palladium on carbon (0.50 g) for 10 minutes at 3 atm. Reaction mixture was filtered through celite and diluted with 1.5 L diethyl ether. Product was filtered and dried under vacuum to give bright yellow solid, 2.23 g (80%):M.P. 262°-263° C. (dec); GC-MS: 313 (M+), 315 (M+ +2); Calc. C16H13ClN4O.HCl: C,55.03; H,4.04; N,16.04; Found: C,55.18; H,4.28; N,16.13.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[OH:38])=[O:3].S(OC)(O[CH3:43])(=O)=O.[OH-].[K+]>C1COCC1>[NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:43])=[O:3]
Reactant: COS(=O)(=O)OC
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 73 is treated with dimethyl sulfate and KOH in THF under the conditions described in Example 61. Chromatographic purification of the crude product on silica gel using ethyl acetate/hexane (4:6) as eluant affords the product.
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc2nc(Cl)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling a reaction mass was poured into a mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 1) and ammonia solution (˜800 ml), after that pH was adjusted to 5.6 with ammonia solution. Precipitate was filtered and rinsed with water. Yield was 39.5 g (84%).