Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[CH:14]1[C:10]2[C:11](=[O:12])[C:7]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:1](=[O:8])[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
In spite of its already high degree of purity, the direct mixing of the crude o-benzoyl-benzoic acid with hot concentrated sulfuric acid gives a strongly colored anthraquinone contaminated with decomposition products. The crude acid is therefore esterified with methanol, and the methyl ester separated from the by-products through a distillation. The esterification may be effected in the conventional manner in the presence of acid catalysts such as hydrochloric, sulfuric or p-toluenesulfonic acids, or alternatively without catalysts under pressure at temperatures above 200° C. The pure o-benzoyl-benzoic acid methyl ester distills off in the range 177°-181° C. under a pressure of 8 Torr. It solidifies to colorless crystals with a melting point of 52.5° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C)C=O>[Si:19]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])[CH2:7][CH2:8]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CO)CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-4-(Hydroxymethyl)-N-methoxy-N-methylcyclohexanecarboxamide (403 mg, 2.00 mmol) in N,N-dimethylformamide (4 mL) was mixed with tert-butylchlorodiphenylsilane (514 μL, 2.00 mmol) and 1H-imidazole (136 mg, 2.00 mmol) under cooling with ice and stirred for one day while the temperature was gradually raised to room temperature. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1 (v/v)) to give the title compound as a colorless oil (536 mg, yield 61%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:15]([O:14][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
Sodium hydride (1.16 g, 29.12 mmol) was added to 6-bromo-2-naphthol (5.00 g, 22.41 mmol) in anhydrous N,N-dimethylformamide (162 mL) at 0° C. After 15 minutes, benzyl bromide (2.40 mL, 3.45 g, 20.18 mmol) was added and the reaction warmed to room temperature over 18 hours. The reaction was diluted with EtOAc (500 mL), saturated aqueous NaHCO3 (200 mL) was added, and the solution was extracted with EtOAc (3×500 mL). The combined organic layers were washed with water (3×1 L), saturated aqueous NaCl solution (1 L), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 5:1 Hexanes:CH2Cl2) to give 36 as a colorless amorphous solid (5.71 g, 90%): 1H NMR (CDCl3, 500 MHz) δ 7.94 (d, J=1.9 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.53-7.47 (m, 3H), 7.46-7.40 (m, 2H), 7.37 (m, 1H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 5.18 (s, 2H); 13C NMR (CDCl3, 125 MHz) δ 157.2, 136.8, 133.2, 130.3, 129.9, 129.9, 128.9 (2C), 128.8, 128.7, 128.4, 127.8 (2C), 120.3, 117.4, 107.3, 70.3; IR (film) νmax 1585, 1452, 1256, 1219, 1204, 1165, 1065, 997, 924, 852, 820, 800, 733, 698, 476 cm−1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].C(Cl)(Cl)Cl.CO>CN(C=O)C.O>[C:18]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:21])[CH:19]=[CH2:20]
Reactant: C=CC(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: C=CC(=O)NCc1ccc(C(=O)O)cc1
Reaction time: 96 h
Yield: 10.3 %

Procedure:
To a stirred solution of 4-aminomethyl benzoic acid (5 g, 33.0 mmol) and pyridine (1.5 mL) in DMF (35 mL) was added acryloyl chloride (2.97 g, 33.0 mmol) at 0° C. dropwise. The reaction mixture was allowed to come to room temperature and stirred further for 4 days. After that it was poured in water (100 mL) and stirred for 15 min and then extracted with EtOAc (3×150 mL). The combined organic extract was washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude product. Column chromatography (silica, 230-400, mixtures of CHCl3/MeOH) provided the desired product (0.7 g, 9.95%) as a white solid which was used for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[S:23](=[O:26])(=[O:25])[NH2:24])(=[O:12])=[O:11])=[C:4]([O:27][CH3:28])[CH:3]=1.[CH3:29]O>S(Cl)(Cl)=O>[CH3:29][O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([NH:13][S:10]([CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[O:27][CH3:28])(=[O:12])=[O:11])=[C:15]([S:23](=[O:25])(=[O:26])[NH2:24])[CH:16]=1
Reactant: COc1cc(Cl)ccc1CCS(=O)(=O)Nc1ccc(C(=O)O)cc1S(N)(=O)=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NS(=O)(=O)CCc2ccc(Cl)cc2OC)c(S(N)(=O)=O)c1
Yield: 97 %

Procedure:
To a solution of 4-[2-(4-chloro-2-methoxy-phenyl)-ethanesulfonylamino]-3-sulfamoyl-benzoic acid (0.18 g, 0.40 mmol) in anhydrous methanol (15 mL), thionyl chloride (1 mL) was added and the mixture was heated at reflux for 18 hours. The volatiles were removed under reduced pressure to give 0.18 g (97% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[F:15][C:16]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=1[NH2:18]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:18][C:17]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:16]=2[F:15])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1cc(F)ccc1F
Reactant: Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cc(F)ccc2F)cc1

Procedure:
First, p-toluic acid is converted to an acid chloride with thionyl chloride. The acid chloride is reacted with 2,5-difluoroaniline to form 4-methyl-2',5'-difluorobenzanilide (V). The compound (V) is then reacted with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide (Lawesson's reagent) to form 4-methyl-2',5'-difluorobenzothioanilide (VI) which is then reacted with potassium tert-butoxide to form 2-(4-methylphenyl)-5-fluorobenzothiazole (VII). The compound (VII) is then reacted with a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide or bromine to form a compound (VIII). Finally, the compound (VIII) is reacted with an excess of triethyl phosphite to produce the compound of formula (IV)-1 in which Y is a fluorine atom.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[CH:6][CH:7]=1.[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13](O)[CH:12]=1.B(O)(O)O>O>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]2[O:10][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:16]=3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(O)cc1
Agent: OB(O)O
Solvent: O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 12 h

Procedure:
68 g (0.5 mole of p-toluic acid were heated with 54.5 g (0.5 mole) of p-aminophenol and 2 g of boric acid in 750 ml of 1,2-methylnaphthalene and the water that formed was eliminated slowly by azeotropic destillation. After heating for 6 hours, 1 g of boric acid were added. After 12 hours, 16 ml of H2O (98%) passed over. The solvent was then removed until dryness, the residue was dissolved in 750 ml of ethanol, clarified with silica gel while still hot, and combined after filtration, while still hot, with 500 ml of H2O. After cooling and filtration with suction at room temperature and washing with aqueous ethanol, there were obtained 89.4 g (85.6% of the theory) of 2-p-tolyl-benzoxazole melting at 113° to 114° C. ##STR41##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([NH2:12])[CH:10]=2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1.[Cl:22][C:23]1[C:28]([C:29](O)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:22][C:23]1[C:28]([C:29]([NH:12][C:9]2[CH:10]=[C:11]3[C:3]([O:2][CH3:1])=[N:4][N:5]([CH2:13][C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)[C:6]3=[N:7][CH:8]=2)=[O:30])=[C:27]([F:32])[C:26]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])=[CH:25][CH:24]=1
Reactant: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)O)c1F
Reactant: COc1ccc(Cn2nc(OC)c3cc(N)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc3c(c2)c(OC)nn3Cc2ccc(OC)cc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
3-Methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-amine (0.020 g, 0.070 mmol), 6-chloro-2-fluoro-3-(propylsulfonamido)benzoic acid (0.023 g, 0.077 mmol), EDCI (0.015 g, 0.077 mmol), and HOBt (0.010 g, 0.077 mmol) were dissolved in DMF (1.0 mL) and stirred for two days at room temperature. The solution was partitioned between water and EtOAc. The organic layers were washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil. The residue was purified by column chromatography (2:1 hexanes/EtOAc) giving 6-chloro-2-fluoro-N-(3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.027 g, 68%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[O:7][C:5](=O)[C:4]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:3]12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O.C(O)C>CS(C)=O>[CH3:1][N:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[C:5](=[O:7])[N:14]2[CH2:21][CH2:20][CH2:19][CH:15]2[C:8]1=[O:9]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Solvent: CS(C)=O
Solvent: CCO
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
The N-methyl isatoic anhydride (I) and L-proline (II) are reacted in a solvent such as ethanol or dimethyl sulfoxide at 25° to 200° C. for a period of 1 to 24 hours to produce the dextrorotatory isomer of the 1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.
Reaction SMILES: C[C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]C(Cl)=O.Cl>N1C=CC=CC=1>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:4](=[O:9])[CH2:5][C:6]([O:7][CH2:2][CH3:10])=[O:8]
Reactant: COCCOCC(=O)Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCCOC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2,2-Dimethyl-1,3-dioxane-4,6-dione (1.72 g) was suspended in anhydrous pyridine (20 ml) and cooled to 0° C. (2-methoxyethoxy)acetyl chloride (2 g) was added slowly. The mixture was stirred at room temperature for 3 h. The mixture was poured into 2 N HCl (30 ml) and extracted with DCM (×3). The combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The orange oil was dissolved in EtOH (20 ml) and was refluxed for 7 h. The solvent was removed in vacuo and the brown oil was Kugelrohr distilled affording the title compound as a colourless oil (1.55 g).
Reaction SMILES: [S:1]([CH2:5][C:6]([NH2:8])=[S:7])(=[O:4])(=[O:3])[NH2:2].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:13](=O)[CH2:14]Br>C(O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:13]2[N:8]=[C:6]([CH2:5][S:1]([NH2:2])(=[O:4])=[O:3])[S:7][CH:14]=2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: NC(=S)CS(N)(=O)=O
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: NS(=O)(=O)Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1

Procedure:
A mixture of sulfamoylthioacetamide (7.7 g., 0.05 mol) and 3,4-dichlorophenacyl bromide (13.4 g., 0.05 mol) in ethanol (50 ml) was heated at reflux for 2 hours. After cooling and filtration there was obtained 11.5 g. of the desired intermediate, m.p. 187°-190° C.
Reaction SMILES: C[O:2][N:3]=[C:4]1[C:16]2[C:11](=[CH:12][C:13]([CH2:19][CH3:20])=[C:14]([OH:18])[C:15]=2[CH3:17])[O:10][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5]1.Cl.O.O1CCOC[CH2:24]1>>[CH2:19]([C:13]1[CH:12]=[C:11]2[C:16]([CH:4]([N:3]([OH:2])[CH3:24])[CH2:5][C:6]3([O:10]2)[CH2:9][CH2:8][CH2:7]3)=[C:15]([CH3:17])[C:14]=1[OH:18])[CH3:20]
Reactant: CCc1cc2c(c(C)c1O)C(=NOC)CC1(CCC1)O2
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CCc1cc2c(c(C)c1O)C(N(C)O)CC1(CCC1)O2

Procedure:
To a mixture of 7-ethyl-6-hydroxy-5-methylspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime (530 mg) and BH3 pyridine complex (8 M, 2 mL) at 0° C., was added a solution of HCl in dioxane (4 M, 8 mL) at 1.5 mL/h. The mixture was cooled with ice-water bath, water was added to quench it, and extracted with ethyl acetate. The organic layer was washed with water, dried, and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 7-ethyl-4-(hydroxy(methyl)amino)-5-methylspiro[chroman-2,1′-cyclobutan]-6-ol as a clear oil (412 mg) 1H-NMR (300 MHz, CDCl3) δ=6.57 (s, 1H), 5.25 (br., 1H), 4.30 (s, 1H), 3.63 (s, 3H), 2.67 (m, 4H), 2.2-1.7 (m, 9H), 1.19 (t, J=7.5 Hz, 3H) ppm. 13C-NMR (75 MHz, CDCl3) δ=148.20, 145.41, 131.08, 122.82, 115.47, 114.99, 61.94, 52.60, 35.63, 34.36, 32.54, 23.14, 13.76, 13.66, 11.41 ppm. MS (m/z)=231 (100, M−N(OH)CH3).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH2:5].Cl.Cl[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH3:1][N:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][CH2:4][N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: ClCc1ccccn1
Reactant: CNCCN
Agent: Cl
Product: CN(CCN(Cc1ccccn1)Cc1ccccn1)Cc1ccccn1

Procedure:
Prepared from N-methylethane-1,2-diamine and 2-chloromethylpyridine hydrochloride using the procedure described by I. Bernal et al in J. Chem. Soc., Dalton. Trans., 1995, 3667.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(N2CCCC2)cc1
Temperature: 80 °C
Yield: 25.2 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g), 1,4-dibromobutane (2.59 g), potassium carbonate (0.35 g) and potassium iodide (0.5 g) in DMF (10 ml) was heated at 80° C. for 5 hours under stirring, and then evaporated in vacuo. After addition of 30% aqueous methanol to the residue, the resulting precipitates were collected by filtration and recrystallized from a mixture of methanol and chloroform (7:3) to give 6-(4-pyrrolidinophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.65 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C:20]#[N:21])=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CCCCCC>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2([C:20]#[N:21])[CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: N#CC1(c2cn(Cc3ccccc3)c3ccccc23)CCCC1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium hydride (60%, 2.26 g, 56 mmol) was added a solution of 1-benzyl-1H-indol-3-ylacetonitrile in DMSO-ether (10 MI: 80 mL) dropwise and the mixture was stirred for 5 hours at 20° C. Water and hexane were added. Solid was collected by filtration and washed with water and hexane to give 1-(1-benzyl-1H-indol-3-yl)cyclopentanecarbonitrile (5.3 g). MS (ES): 301 (MH+).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]([CH2:10][CH3:11])[C:4](=[O:12])[C:3]=1[CH3:13].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.[H-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[CH2:10]([N:5]1[C:4](=[O:12])[C:3]([CH3:13])=[C:2]([O:1][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[N:7]=[C:6]1[S:8][CH3:9])[CH3:11]
Reactant: CCn1c(SC)nc(O)c(C)c1=O
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCn1c(SC)nc(OCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.4 %

Procedure:
In 10 ml of hexamethylphosphoric triamide were dissolved 1 g of 6-hydroxy-3-ethyl-5-methyl-2-methylthio-4(3H)-pyrimidinone and 1.66 g of 4-(4'-trifluoromethylphenoxy)benzyl bromide and thereto was added 0.3 g of sodium hydride (55% in mineral oil). The mixture was stirred for 15 hours at room temperature. The resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 2.1 g of crystals. The crystals were recrystallized from a mixture of hexane and ethyl ether (3:1 ) to give 0.6 g of the intended product.
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([NH:14][CH:15]([CH3:17])[CH3:16])[N:7](C(OCC)=O)[C:6]=2[S:5][C:4]=1[CH3:23])#[N:2].[OH-].[Na+]>>[C:1]([C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([NH:14][CH:15]([CH3:16])[CH3:17])[NH:7][C:6]=2[S:5][C:4]=1[CH3:23])#[N:2]
Reactant: CCOC(=O)N1C(NC(C)C)=NS(=O)(=O)c2c1sc(C)c2C#N
Agent: [Na+]
Agent: [OH-]
Product: Cc1sc2c(c1C#N)S(=O)(=O)N=C(NC(C)C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 7-cyano-3-isopropylamino-6-methyl-4H-thieno[2,3-e]-1,2,4-thiadiazine-4-carboxylate 1,1-dioxide (0.15 g) and 5 ml of 1 M aqueous sodium hydroxide was stirred at room temperature for 1 h. Then the mixture was filtered and pH was adjusted to 1-2 by dropwise addition of 4M hydrochloric acid. After stirring for 30 min the precipitate was filtered off, rinsed with a small amount of water and dried to give the title compound; m.p. m.p. 235-238° C.; 1H-NMR (DMSO-d6) δ(ppm): 11.35 (s, 1H, NH), 7.55 (br d, 1H, NH), 3.98-3.77 (m, 1H, CH), 2.50 (s, 1H, CH3), 1.15 (d, 6H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:31])[C@@H:16]([NH:23]C(OC(C)(C)C)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])[CH3:2].[ClH:32].O1CCOCC1>>[ClH:32].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:31])[C@@H:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (S)-1-((S)-2-tert-butoxycarbonylamino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester (2.78 g, 6.55 mmol, Eq: 1) was added 4 M HCl in dioxane (16.4 mL, 65.5 mmol, Eq: 10). The mixture was stirred at rt for 2 h. The solvent was removed in vacuo. After drying under vacuum, (S)-1-((S)-2-amino-2-phenyl-acetyl)-2,3-dihydro-1H-indole-2-carboxylic acid ethyl ester hydrochloride was obtained as an off-white solid which was used for next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:41])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:32]2[CH:31]=[C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:41])[NH:19][C:9]5[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)[CH:35]=[CH:34][N:33]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C4CCCC4)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M271) (360 mg, 0.619 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (135 mg, 47%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].I[CH2:14][CH2:15][CH3:16]>>[CH2:14]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10])[CH2:15][CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CCCI
Product: CCCn1cc([N+](=O)[O-])cc1C(=O)OC
Yield: 63.7 %

Procedure:
Following the basic procedure of Example 25(d), by reacting 1.79 g (10.5 mmol) of methyl 4-nitro-2-pyrrolecarboxylate with 1.23 ml (12.6 mmol) of 3-iodopropane, 1.42 g (64%) of the expected compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:13]=2[N:14]=1)[CH2:5][CH2:6][C:7](=O)[CH3:8].C([O-])(=O)C.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].Cl.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:12]2[O:11][C:10]([N:4]3[CH2:5][CH2:6][CH:7]([CH3:8])[NH:1][CH2:2][CH2:3]3)=[N:14][C:13]=2[CH:15]=1
Reactant: CC(=O)CCN(CCN)c1nc2cc(Cl)ccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1CCN(c2nc3cc(Cl)ccc3o2)CCN1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
Bis-MSA adduct 12 (17.19 kg, 36.27 mol), sodium acetate (2.97 kg, 36.3 mol) and DCM (152 kg, 115 L) were charged to a vessel. The resulting slurry was cooled to 15° C. and acetic acid (26.8 kg, this was the amount required for dissolution of the salt) was added maintaining an internal temperature below 20° C. The batch was cooled to 15° C. and Na(OAc)3BH (9.25 kg, 43.6 mol) was charged via a glove bag over 30 min maintaining an internal temperature below 20° C. The resulting solution was aged for 30 min at 20° C., HPLC analysis showed the reaction to be complete. The batch was then cooled to 10° C., 2N HCl (38.80 kg) was added and the resulting solution was aged for 30 min at 10° C. The mixture was then adjusted to pH 9 using 5 N NaOH maintaining an internal temperature below 20° C. Once at pH 9 the layers were allowed to separate and the organic lower layer was ran off into a clean drum. DCM (76.2 kg, 57.5 L) was then added to the aqueous phase, the layers were mixed, allowed to separate, then the lower layer was combined with the previous organics (this step was repeated but HPLC of the third DCM layer showed that this was unnecessary as it only contained 12.5 g of rac-11 by assay). The combined DCM fractions were then charged to a 160 liter vessel and distilled to approximately 20 L (˜1 volume of DCM). THF (44 kg) was charged to the vessel and the resulting stream was discharged into a clean drum and stored in the cold room prior to the next step in the reaction sequence. The final solution was found to contain 9.4 kg of rac-14. This stream was sufficiently pure to be used directly in the subsequent resolution.