Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[S:12])[NH:10][NH2:11])[CH:2]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9](=[S:12])[NH:10][N:11]=[CH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:2]=1
Reactant: NNC(=S)NCc1cccnc1
Reactant: O=Cc1ccccn1
Solvent: CC(=O)O
Product: S=C(NCc1cccnc1)NN=Cc1ccccn1

Procedure:
The title compound was prepared from a mixture of 4-(3-picolyl)-3-thiosemicarbazide (100 mg, 0.549 mmol), 2-pyridinecarboxaldehyde (52 μL, 0.549 mmol) and glacial acetic acid (62 μL) similar to Example 3 and isolated as a white solid (87 mg, 58%). 1H NMR (DMSO-d6): 11.76 (s, 1H), 9.18 (t, J=6.0 Hz, 1H), 8.45-8.43 (m, 2H), 8.33 (dd, J=1.7, 4.7 Hz, 1H), 8.15 (d, J=8.4 Hz, 1H), 8.0 (s, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.28-7.22 (m, 2H), 4.74 (d, J=6.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1(C(OCC)=O)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[I-].[Li+].[C-]#N.[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: [C-]#N
Agent: [I-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOCC1
Temperature: 140 °C
Yield: 91.9 %

Procedure:
To a solution of tetrahydropyran-4,4-dicarboxylic acid diethyl ester (400 mg, 1.74 mmol) in N,N-dimethylformamide (4 mL), was added lithium iodide (1.16 g, 8.66 mmol), followed by sodium cyanide (94 mg, 1.91 mmol). The mixture was heated at 130° C. for 7 hours, 140° C. for 25 hours, after which GC analysis indicated the reaction to be >95% complete. The mixture was partitioned between 33% diethyl ether/hexanes (100 mL) and brine (25 mL). The organic layer was washed with additional brine (25 mL), dried (MgSO4) and concentrated in vacuo to afford the tetrahydropyran-4-carboxylic acid ethyl ester (253 mg, 92%). Note: Substitution of 2 equivalents of sodium acetate for 1.1 equivalents of sodium cyanide in this reaction and heating 12 hours longer provides identical results.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[CH2:6][CH3:7])C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:13][C:8]1([CH:5]([CH2:6][CH3:7])[CH2:4][OH:3])[O:9][CH2:10][CH2:11][O:12]1
Reactant: CCOC(=O)C(CC)C1(C)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC(CO)C1(C)OCCO1

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-butyric acid ethyl ester (85.5 g) was taken up in dry Et2O (50 mL). This mixture was added dropwise to a suspension of LiAlH4 (16.1 g) in dry Et2O (200 mL), cooled in an ice bath. The mixture was refluxed for 4 h., cooled in an ice bath, and quenched by adding H2O (16.1 mL), 2M aqueous NaOH (32.2 mL) and again H2O (16.1 mL). The suspension was filtered, the filter cake was washed with Et2O, and the combined filtrates were evaporated to dryness. The residue (49 g) was purified by vacuum distillation (112-125° C., 15 mbar), yielding 43.5 g of a clear, colorless liquid. 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J=7.5 Hz, 3H), 1.10-1.24 (m, 1H), 1.31 (s, 3H), 1.50-1.75 (m, 2H), 3.12, (br s, 1H), 3.59-3.76 (m, 2H), 3.94-4.02 (m, 4H).
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]=2[CH:11]=1>O1CCOCC1.[Cu]I>[I:2][C:10]1[CH:22]=[CH:21][C:13]2[S:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:12]=2[CH:11]=1
Reactant: COC(=O)c1cc2cc(Br)ccc2s1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2cc(I)ccc2s1

Procedure:
Under an argon atmosphere 0.35 g (1.84 mmol) of CuI, 5.53 g (36.88 mmol) of NaI, and 0.39 mL (3.67 mmol) of N,N′-dimethylethylenediamine were added to a solution of 5.0 g (18.4 mmol) of methyl 5-bromobenzo[b]thiophen-2-carboxylate in 18 mL of 1,4-dioxane and after rinsing again with argon the reaction mixture was heated overnight to 110° C. After cooling, the reaction mixture was combined with 30% aqueous ammonia and water, exhaustively extracted with EtOAc, and the combined organic phases were twice washed with water and dried over magnesium sulfate. After the desiccant and solvent had been eliminated, the residue was triturated with DIPE and MTBE, suction filtered, and dried in the air. Yield: 3.4 g (58% of theoretical); C10H7IO2S (M=318.132); calc.: molpeak (M)+: 318; found: molpeak (M)+: 318; HPLC-MS: 6.4 minutes (method B).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][Si:8]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[CH2:9][CH2:10][CH2:11][NH2:12])[CH3:6].N1C=CC=CC=1>C(OCC)C>[CH2:14]([O:13][Si:8]([O:16][CH2:17][CH3:18])([O:7][CH2:5][CH3:6])[CH2:9][CH2:10][CH2:11][N:12]=[C:1]=[O:2])[CH3:15]
Reactant: CCO[Si](CCCN)(OCC)OCC
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCO[Si](CCCN=C=O)(OCC)OCC
Yield: 70.1 %

Procedure:
In 150 ml of ethyl ether was dissolved 9.9 g of carbonyl chloride, and a solution of 22.1 g of γ-triethoxysilylpropylamine and 18.2 g of pyridine in 50 ml of ethyl ether was dropped into the above solution at -5° C. to -10° C. over a period of 3 hours to effect reaction. After the reaction, the crystal of pyridine hydrochloride was removed by filtration and the filtrate was distilled to recover ethyl ether, whereby 17.3 g of γ-triethoxysilylpropyl isocyanate was obtained as a fraction having a boiling point of 95° C. to 100° C. under 8 mmHg.
Reaction SMILES: C([O:8][C:9](=[O:40])[CH:10]([O:37][CH2:38][CH3:39])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](=[O:35])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:23][CH:22]=2)=[C:14]([CH3:36])[CH:13]=1)C1C=CC=CC=1.CO>CCOC(C)=O>[C:31]([O:30][C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([O:37][CH2:38][CH3:39])[C:9]([OH:40])=[O:8])=[CH:13][C:14]=2[CH3:36])=[O:35])=[CH:26][CH:25]=1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(C)c1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(C)c1)C(=O)O

Procedure:
The title compound was prepared from 3-{4-[2-(4-tert-butoxycarbonylamino-phenyl)-acetoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid benzyl ester (0.035 g, 0.064 mmol) in the same manner as described for example 1 with the difference that MeOH was used as the solvent instead of EtOAc. The crude product was purified by column chromatography using DCM/iPrOH (95:5) as the eluent and the title compound was obtained as a solid (0.02 g, 68.4%). 1H NMR (500 MHz, CD3OD): δ 7.40-7.42 (d, 2H), 7.29-7.31 (d, 2H), 7.10-7.15 (m, 2H), 6.86-6.87 (d, 1H), 3.84-3.88 (m, 3H), 3.60-3.62 (m, 1H), 3.26-3.29 (m, 1H), 2.96-3.02 (dd, 1H), 2.80-2.86 (dd, 1H), 1.53 (s, 9H), 1.10-1.13 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[CH:4][N:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=1.[H-].[Na+]>CC(N(C)C)=O>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:22][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:6][N:5]=[CH:4][N:3]=2)=[CH:19][CH:18]=1
Reactant: Clc1ncncc1Oc1ccccc1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(COc2ncncc2Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
To a solution of 4-chloro-5-phenoxypyrimidine (0.4 g, 1.9 mmol) described in JP-A-49-92080 and 4-trifluoromethylbenzylalcohol (0.36 g, 2.0 mmol) in dimethylacetamide (7 m) was added sodium hydride (0.093 g, 2.3 mmol) at 0° C., and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-(4-trifluoromethylbenzyloxy)-5-phenoxypyrimidine (0.60 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]Cl)=[CH:5][CH:6]=1.BrCC1CCCCO1.[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][C:25](=[O:28])[C:24]12[C:32]2=[CH:33][C:34]3[O:38][CH2:37][O:36][C:35]=3[CH:39]=[C:31]2[O:30][CH2:29]1>>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:26]2[C:27]3[C:23](=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]([F:40])([F:17])[F:41])[C:24]3([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]3)[C:25]2=[O:28])=[CH:5][CH:6]=1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(Cl)s1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc(Cl)s2)c2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-chloro-5-(chloromethyl)thiophene to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(5-chloro-2-thienyl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (95%) as a colorless solid: mp 165-166° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.66 (d, J=8.0 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.24 (dd, J=7.8, 7.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 6.80 (d, J=3.8 Hz, 1H), 6.70 (s, 1H), 6.22 (s, 1H), 5.91 (d, J=4.4 Hz, 2H), 5.09 (ABq, 2H), 4.78 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ178.9, 156.2, 149.2, 142.4, 139.9 (2C), 138.7, 135.4, 129.1, 127.4, 127.2, 126.9, 125.9, 123.9, 119.4, 111.5, 103.5, 102.0, 93.9, 80.7, 56.5, 42.3; MS (ES+) m/z 481.2 (M+1), 479.9 (M+1).
Reaction SMILES: [CH:1]([C:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)=[O:5])([CH3:3])[CH3:2].CC(C)=O>C(O)C>[OH:5][CH:4]([C:6]1[C:7]([C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)C(=O)c1cncnc1C(F)(F)F
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)C(O)c1cncnc1C(F)(F)F
Reaction time: 2 h
Yield: 86.9 %

Procedure:
25 g (115 mmol) of 5-isopropylcarbonyl-4-trifluorometylpyrimidine was dissolved in 100 ml of ethanol, and under cooling with ice, 6 g (69 mmol) of a borane-tert-butylamine complex was added, followed by stirring for 2 hours. Further, 20 ml of acetone was added, followed by stirring for 0.5 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent/n-hexane:ethyl acetate=1:1) to obtain 22 g (yield: 87%) of 5-(1-hydroxy-2-methylpropyl)-4-trifluoromethylpyrimidine as slightly yellow liquid (nD20=1.4481)
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[F:25][C:19]1[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=1[C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:26])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cc(F)ccc3F)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2cc(F)ccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 71 %

Procedure:
As described for example 265f, 6-[3-(2,5-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (170 mg, 71%) which was obtained as a colourless oil. MS: m/e=430.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])=[CH:7][CH:6]=2)[C:14](=[O:15])[CH2:13]1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2)c2ccc3c(c2N1)CCCC3
Temperature: 80 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (190 mg, 0.59 mmol) obtained in Example 10, o-nitrobenzenesulfonyl chloride (197 mg, 0.89 mmol), and dry pyridine (5 mL) were mixed. The mixture was stirred at 80° C. for 17 hours. Pyridine was removed by evaporation under reduced pressure. To the residue was added water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give the titled compound as pale yellow crystal (233 mg, yield 78%).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1.[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>CN1CCCC1=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:17]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:16]=1)=[CH2:18]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)NCCc1coc2ccc(I)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2occ(CCNC(C)=O)c2c1

Procedure:
15 mmol of the product obtained in Step B, 16 mmol of vinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladium are heated for 3 hours at 110° C., with stirring, in 30 ml of N-methylpyrrolidinone. After removal of the solvent by evaporation, the residue is taken up in 20 ml of dichloromethane and treated with an aqueous 10% potassium fluoride solution. Extraction, concentration under reduced pressure and chromatography on silica gel yield the pure title product.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:20])[CH2:17][CH2:18][CH3:19]>>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(2-dimethylamino-ethylamino)-nitrobenzene and butyryl chloride
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[Br:16]Br.C(=O)(O)[O-].[Na+]>CCOCC>[Br:16][CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][CH2:11][Cl:12])=[CH:7][C:2]=1[F:1])=[O:15]
Reactant: CC(=O)c1ccc(OCCCCl)cc1F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(OCCCCl)cc1F
Reaction time: 17 h

Procedure:
A solution of the product of Step A (2.3 g) in ether (10 mL) was treated with bromine (0.51 mL) and the mixture stirred for approximately 17 hours. The mixture was slowly poured into saturated sodium bicarbonate solution (40 mL) and then the organic layer was separated. The aqueous layer was washed with a fresh portion of ether (40 mL). The combined organic layers were washed with a fresh portion of water (50 mL), dried over magnesium sulfate, filtered and evaporated to give the title compound (3.1 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:19](Cl)(=[O:21])=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:23]>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:19]([NH2:23])(=[O:21])=[O:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a stirred solution of 10 g (0.0281 mole) of 1-phenylsulfonyl-1H-indole-2-sulfonyl chloride in 150 ml anhydrous THF was added at -78° 4 ml (0.192 mole) of anhydrous ammonia. The resulting slurry was allowed to warm to room temperature over 30 minutes, then was sparged with nitrogen to remove excess ammonia. The slurry was filtered and the filtrate evaporated in vacuo to afford 9.19 g of tan solid, m.p. 199°-200.5°, 1H NMR (CDCl3 /DMSO-d6) δ7.23-7.77 (m, 9H), 8.1-8.28 (m, 3H C-3 proton and SO2NH2). The infrared spectrum of the product included absorptions at 3400 and 3280 cm-1 (SO2NH2).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH2:17][CH:18]3CCNC[CH2:19]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.C=O>C(O)=O>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:24][CH3:25])=[C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:5]([CH3:6])[CH2:4][CH2:3]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OCC1CCNCC1
Agent: C=O
Solvent: O=CO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C)CC1
Temperature: 90 °C
Yield: 40 %

Procedure:
6-{[(1-tert-Butoxycarbonyl)piperidin-4-yl]oxy}-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline (Reference Example 3; 300 mg, 0.66 mmol) was dissolved in formic acid (10 ml). Aqueous formaldehyde solution (40%, 1 ml) was added, and the mixture heated to 90° C. for 3 hours. The mixture was evaporated, and the residue dissolved in water (30 ml). The solution was adjusted to pH 8-9 by the addition of sodium hydroxide solution (1M), causing precipitation of a white solid; this was collected by filtration and washed with water (20 ml). The crude product was purified by chromatography, eluting with 0 to 2.5% (7:1 MeOH/concentrated aqueous NH4OH) in DCM. Evaporation of the appropriate fractions followed by crystallisation of the residue from acetonitrile gave the product as a white crystalline solid (55 mg, 20%); 1H NMR: 1.66-1.76 (m, 2H), 1.95-2.05 (m, 2H), 2.14-2.22 (m, 2H), 2.18 (s, 3H), 2.65-2.70 (m, 2H), 3.92 (s, 3H), 4.51 (m, 1H), 7.19 (s, 1H), 7.26 (dd, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.78 (s, 1H), 8.34 (s, 1H), 9.53 (s, 1H); Mass Spectrum: 417.2, 419.3
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])[OH:5])[CH2:3][CH2:2]1>CC(C)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[CH:1]1([C:4]([C:6]2[C:7]([Cl:13])=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])=[O:5])[CH2:2][CH2:3]1
Reactant: OC(c1c(Cl)ncnc1Cl)C1CC1
Agent: [Cr+3]
Agent: [O-2]
Solvent: CC(C)=O
Product: O=C(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
Add chromium oxide (VI) (5.84 g, 58.4 mmoles) portion wise to cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (4.0 g, 18.2 mmoles) in 80.0 mL acetone at 0° C. and stirr for 30 min at 0° C. Next add isopropyl alcohol to quench the excess reagent and stir for another 15 min at room temperature. Cool to 0° C. and pour onto sat. NaHCO3 solution. Filter through Celite® bed, extract with ethyl acetate (3×50 mL), and wash the combined organic layers with saturated aqueous sodium chloride. Dry and concentrate under reduced to give the title compound as a colorless oil (2.0 g, Yield 50%, 9.2 mmol).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][S:5]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[C:15]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:16]3[C:23]4[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=4[CH2:21][N:20]([CH3:30])[CH2:19][CH2:18][N:17]3[C:31]=2[CH:32]=1)=[O:10])(=[O:7])=[O:6].O.[OH-].[Na+].Cl>O1CCOCC1>[CH:33]1([C:15]2[C:14]3[CH:13]=[CH:12][C:11]([C:9]([NH:8][S:5]([CH2:4][C:3]([OH:39])=[O:2])(=[O:7])=[O:6])=[O:10])=[CH:32][C:31]=3[N:17]3[CH2:18][CH2:19][N:20]([CH3:30])[CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=4[C:16]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)CS(=O)(=O)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C)Cc1cc(OC)ccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(C)CCn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)CC(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of methyl({[(14-cyclohexyl-3-methoxy-6-methyl-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}sulfonyl)acetate (from example 5) in dioxane (0.04 M) was added an equal volume of water and 4 eq of NaOH (1 N aqueous solution). The reaction was stirred vigorously at RT for 1 h. The reaction was acidified with aqueous HCl (1 N) and reduced in vacuo to remove dioxane. The resultant aqueous slurry was diluted with MeCN and water and freeze dried to leave a white powder. 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 (72%).
Reaction SMILES: [C:1]([C:3]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].Cl[C:24]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.CC(C)([O-])C.[K+].Cl>O1CCCC1>[C:6]([CH:5]1[CH2:4][C:3]([C:1]#[N:2])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:9][CH2:10][C:11]1=[O:13])([O:8][CH3:24])=[O:7]
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Reactant: COc1ccc(CC(C#N)(CCC(=O)O)CCC(=O)O)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(Cc2ccc(OC)cc2)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 53.94 gm. (0.169 mole) of the dimethyl ester of 4-cyano-4-(p-anisyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and usig 1100 ml. of the tetrahydrofuran, 38.0 ml. (0.34 mole) of the potassium tert-butoxide, and 270 ml. of the 2.5 N hydrochloric acid instead of the 700 ml., the 24.4 gm. (0.218 mole), and the 175 ml., respectively, there is prepared 46.2 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(p-anisyl)cyclohexanone as a gum.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:73])=[O:72])[CH:68]=[CH:67][C:65]=1[NH2:66]>>[F:63][C:64]1[CH:70]=[C:69]([S:71]([CH3:74])(=[O:72])=[O:73])[CH:68]=[CH:67][C:65]=1[NH:66][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(N)c(F)c1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(S(C)(=O)=O)cc2F)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.36 g, 0.62 mmol), was reacted with diisopropylethylamine (0.64 g, 5 mmol), diphenylphosphinic chloride (0.59 g, 2.5 mmol), then reacted with 2-fluoro-4-(methylsulfonyl)aniline (Matrix) (0.12 g, 0.62 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-fluoro-4-methanesulfonyl-phenyl)-amide as a off white solid (Yield 20 mg, 5%).