Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1>>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:34]=[N:33][CH:32]=[CH:31][N:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnccn1
Product: C[C@@H](c1ccc(-c2cnccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 2-bromopyrazine. LC-MS Method 2 tR=1.249, m/z=374; 1H NMR (CDCl3) 1.12 (s, 3H), 1.28 (s, 3H), 1.58 (m, 3H), 2.19-2.20 (m, 4H), 2.39 (m, 1H), 2.89 (m, 1H), 5.74 (m, 1H), 7.09 (m, 2H), 7.28-7.40 (m, 5H), 7.78 (m, 2H), 8.48 (m, 1H), 8.59 (m, 1H), 8.94 (m, 1H).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.O.C1OCCOCCOCCOCCOCCOC1>[CH:14]1[C:13]([N:8]2[C:7]([NH2:6])=[N:11][CH:10]=[CH:9]2)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: Nc1ncc[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nccn1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 93.1 %

Procedure:
To a solution of 2-aminoimidazole sulfate (2.24 g, 17 mmol) in DMF (30 mL) was added 4-bromo-1-nitrobenzene (3.4 g, 17 mmol), K2CO3 (4.69 g, 34 mmol) and 18-crown-6 (50 mg), and the resulting mixture was stirred at 80° C. for 16 hours. The mixture was cooled to room temperature, and was diluted with EtOAc (150 mL) and water (50 mL). The organic layer was washed with brine (20 mL×5), dried over MgSO4, and concentrated to give 4-(2′-amino-imidazol-1′-yl)nitrobenzene (3.23 g, 98%). 1H NMR (CD3OD) δ 8.38 (d, J=9.1 Hz, 2H), 7.73 (d, J=9.1 Hz, 2H), 6.90 (d, J=1.9 Hz, 1H), 6.66 (d, J=1.9 Hz, 1H); MS(ES+) m/z 205 (M+H, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=O)=[CH:7][N:6]=1)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:27]=[N+:28]=[N-:29])=[O:13])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)O)cn1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C(=O)N=[N+]=[N-])cn1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of pyridine-2,5-dicarboxylic acid-2-methyl ester (0.5 g, 2.76 mmol)) (from Example 83a supra) at −10° C. in acetone (9.16 mL) was added triethylamine (0.385 mL, 2.76 mmol) (Aldrich), followed by the addition of ethyl chloroformate (0.265 mL, 2.76 mmol). (Aldrich). After the mixture was stirred at −10° C. for 30 minutes, an aqueous solution of sodium azide (0.53 g, 8.28 mmol) in water (10 mL) was added. The mixture was warmed up and stirred at room temperature for 1 hour, then concentrated to half volume, extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated to give 5-azidocarbonyl-pyridine-2-carboxylic acid methyl ester as a white solid (Yield 0.47 g, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[N].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)CC.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>[C:15]([CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([O:9][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:33]=[CH:34][C:29]([S:28][CH3:27])=[CH:30][CH:31]=2)=[CH:3][CH:4]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])#[N:16]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [N]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CSc1ccc(-c2ccc([C@H](O[C@@H](CC(C)C)C(=O)NCC#N)c3ccccc3)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide (0.84 mmol, 348 mg) in toluene (5 mL) and n-propanol (1.5 mL) was added under a stream of nitrogen 4-(methylthio)phenylboronic acid (1.0 mmol, 169 mg), Pd(PPh3)4 (0.042 mmol, 48 mg), Na2CO3 (2 M, 2 mL). The mixture was degassed with a rapid stream of nitrogen bubbling through the mixture and the mixture was heated to 100° C. for 2 h. The mixture was cooled, diluted with EtOAc and washed with water. The product was isolated by chromatography (40% EtOac/Hexane).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:16][CH2:17][CH2:18][CH2:19][Cl:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: ClCCCCBr
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCCCl
Yield: 46.4 %

Procedure:
A suspension of 4-chloro-6-methoxyquinazolin-7-ol (0.6 g, 2.86 mmol), 1 bromo 4 chlorobutane (0.63 g, 3.7 mmol), potassium carbonate (1.19 g, 8.6 mmol) and dimethylformamide (10 ml) were heated to 95 C for 1.5 hours. The excess potassium carbonate was filtered off and the reaction evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 60-100% dichloromethane in hexane and 30-50% ethyl acetate in hexane to give 4-chloro-7-(4-chlorobutoxy)-6-methoxyquinazoline as a solid (0.4 g, 47%)
Reaction SMILES: [CH:1]1([CH:7]([O:49][C:50](=[O:53])[CH2:51][CH3:52])[O:8][P:9]([CH2:21][C:22]([N:24]2[C@H:32]([C:33]([O:35]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:34])[CH2:31][C:26]3([S:30][CH2:29][CH2:28][S:27]3)[CH2:25]2)=[O:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:7]([O:49][C:50](=[O:53])[CH2:51][CH3:52])[O:8][P:9]([CH2:21][C:22]([N:24]2[C@H:32]([C:33]([OH:35])=[O:34])[CH2:31][C:26]3([S:27][CH2:28][CH2:29][S:30]3)[CH2:25]2)=[O:23])([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)OC(OP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1)SCCS2)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC(=O)OC(OP(=O)(CCCCc1ccccc1)CC(=O)N1CC2(C[C@H]1C(=O)O)SCCS2)C1CCCCC1
Reaction time: 1.5 h
Yield: 158.4 %

Procedure:
A solution of 1.0 g (1.3 mmol) of (S)-7-[[[cyclohexyl(1-oxopropoxy)methoxy](4-phenylbutyl)phosphinyl]acetyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid, benzhydryl ester in 10 ml of dichloromethane was stirred, cooled in an ice-bath, treated with 0.3 ml of anisole and 1.0 ml of trifluoroacetic acid (dropwise). After 90 minutes, the solvent and bulk of excess of trifluoroacetic acid were removed on a rotary evaporator and the residue was shaken with 50 ml of ethyl acetate and 20 ml of cold water. The layers were separated (5 ml of ether was added to break up the emulsion) and the organic phase was washed with three 20 ml portions of water. After back-extracting the combined aqueous layers with 25 ml of ethyl acetate, the combined organic layers were washed with 20 ml of saturated sodium chloride, dried (MgSO4), and the solvent evaporated to yield 1.26 g of a syrup. The syrup was purified by chromatography on 60 g of silica gel (60-200 mesh, d=0.37 g/ml) using 40:1:1 dichloromethane:methanol:acetic acid to give 0.74 g of a foam-like solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
60 mg (0.14 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 35 mg (0.22 mmol, 1.5 eq.) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reatced according to the General Method 2. Yield: 35 mg (45% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH2:10]1[CH:14]2[CH:15]3C=CC([CH:13]2C=[CH:11]1)C3>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[CH2:13][CH:14]3[CH2:15][CH:7]2[CH:11]=[CH:10]3)=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: Clc1ccc(C2CC3C=CC2C3)cc1

Procedure:
5-(p-Chlorophenyl)norbornene (called "CPN" hereinafter) was prepared from p-chlorostyrene and dicyclopentadiene in a pressure vessel and purified by fractional distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[Cl:37])[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[Cl:37])/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccc(F)cc2Cl)c1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cc(F)cc(Cl)c32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(2-chloro-4-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 5.38 (s, 2H), 6.01 (dd, 1H), 6.80 (dd, 1H), 7.27-7.40 (m, 9H), 7.45-7.50 (m, 3H), 7.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](N2CC[C@@H](O)C2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH2:28]1[C:31]2([CH2:35][CH2:34][NH:33][CH2:32]2)[CH2:30][O:29]1>>[Br:1][C:2]1[C:3]([N:33]2[CH2:34][CH2:35][C:31]3([CH2:30][O:29][CH2:28]3)[CH2:32]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: C1CC2(CN1)COC2
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC3(COC3)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 12.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Example 35) and 2-oxa-6-azaspiro[3,4]octane to afford white needles. UPLC-MS (condition 1) tR=2.93 min, m/z=471.9/473.9 [M+H]+, m/z=469.9/471.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.20 (t, J=6.85 Hz, 2H) 3.73 (t, J=6.97 Hz, 2H) 3.95 (s, 2H) 4.51 (d, J=5.87 Hz, 2H) 4.60 (d, J=5.87 Hz, 2H) 7.35 (d, J=8.31 Hz, 2H) 7.82-7.88 (m, 2H) 8.36 (d, J=2.20 Hz, 1H) 8.69 (d, J=1.96 Hz, 1H) 10.24 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[C-:17]#[N:18].[Na+]>>[C:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:17]#[N:18])[CH:8]=[CH:7][CH:6]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#N
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: [Na+]
Product: N#CCc1cccc(C(=O)c2ccccc2)c1

Procedure:
m-(Bromomethyl)benzophenone is reacted with sodium cyanide to form (m-benzoylphenyl)acetonitrile which is reacted with diethyl carbonate in the presence of sodium ethoxide to form sodium salt of ethyl alpha-cyano(m-benzoylphenyl)acetate. The sodium salt is reacted with methyl iodide to obtain ethyl alpha-cyano-alpha-(m-benzoylphenyl)propionate. The resulting ester is hydrolyzed and then subjected to decarboxylation to form alpha-(m-benzoylphenyl)propionitrile. Alkaline hydrolysis of alpha-(m-benzoylphenyl)propionitrile affords alpha-(m-benzoylphenyl)propionic acid. (For details, see British Patent No. 1,164,585).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1cc(C2(CN3CCOCC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 60 °C
Yield: 35.6 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (207 mg, 0.65 mmol) and bis(2-bromoethyl)ether (82 μL, 1.3 mmol) in anhydrous acetonitrile (10 mL) was added potassium carbonate (180 mg, 1.3 mmol). The mixture was heated to 60° C. overnight then concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with DCM:MeOH (97:3) with 10% NH3 to give the title compound (90 mg, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][NH:8][C:7](=S)[C:6]=2[CH:17]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[CH:17]=1
Reactant: C1CCNC1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(=S)NC2
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(N1CCCC1)=NC2
Yield: 51 %

Procedure:
A stirred mixture of 8-chloro-4,5-dihydro-1-methyl-6H-s-triazolo[4,3-a][1,4]benzodiazepine-6-thione (VIIIa)(2.65 g., 0.01 mole) and pyrrolidine (25 ml.) was refluxed under nitrogen for 10 hours, cooled, mixed with water and extracted with methylene chloride. The extract was washed with water, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in methylene chloride/ethyl acetate, decolorized with charcoal (Darco) and concentrated until the product crystallized. The product was recrystallized from methylene chloride/acetate to give 1.43 g., melting point 223°-225° and 0.10 g., melting point 222°-225° of the titled compound (Ic)(51% yield). The analytical sample had: melting point 223°-225°; uv (EtOH) λ max 210.5 mμ (ε 41,050), 233 (sh 17,700), 287 (sh, 3450), 292 (3550). The ir and nmr spectra support the proposed structure.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccc(C(F)(F)F)cc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-trifluoromethylbenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 588 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[CH:17]=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[C:4]([F:18])[CH:3]=1.[Cl:19]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:19][C:17]1[C:9]([C:5]2[CH:6]=[C:7]([OH:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:18])=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cc(-c2cc3n(n2)CCCC3)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
The product from Step C (8.3 g) was dissolved in dimethylformamide (40 ml) and was treated with N-chlorosuccinimide (4.4 g). The mixture was heated and at 65° C. a color change from yellow to red occurred. Heating was discontinued and the reaction was allowed to stir at room temperature overnight. The reaction mixture was diluted with water and ice and the solid was filtered and washed with water. After air drying the solid was taken up in ethyl acetate and dried further with magnesium sulfate. The ethyl acetate was removed by evaporation at reduced pressure to afford the product as a slightly pink solid (9.2 g), m.p.=177°-178° C. NMR (DMSO-D6): δ10.2 (OH), 7.3 (1H), 6.9 (1H), 3.9 (2H), 2.6 (2H), 1.9 (2H), 1.7 (2H).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:10]([O-])=[CH:11][C:12](=O)[C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]([F:9])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([NH:49][NH2:50])[CH:44]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:10]2[N:49]([C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)[N:50]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(F)cc(Br)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2cccnc2)n1

Procedure:
600 mg (1.30 mmol) of the compound of Example 2A is reacted analogously to the synthesis of the compound of Example 20A with 208 mg (1.43 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 406 mg (86% of theory) of the title compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH2:25])[CH2:22][CH2:21]2>>[F:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH:23]([NH:25][C:2]1[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=3)[N:3]=1)[CH2:22][CH2:21]2
Reactant: NC1CCc2cccc(F)c21
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Product: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
Step C+D: The title compound was prepared in accordance with the general method described in example 2 from 2-chloro-6-nitro-quinoline and rac-7-fluoro-indan-1-ylamine; MS: m/e=294.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[C:7]([N+:22]([O-:24])=[O:23])=[C:8]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17].[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:21][C:19]1[CH:18]=[C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([CH:20]=1)[O:5][C:4]1[C:3]([CH3:28])=[C:2]([NH:1][S:31]([CH2:29][CH3:30])(=[O:33])=[O:32])[CH:27]=[CH:26][CH:25]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1Oc1cc(F)cc(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2[N+](=O)[O-])c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 118 %

Procedure:
1.18 g 3-(3-amino-2-methylphenoxy)-5-fluoro-N-(2-fluoro-4-iodophenyl)-2-nitroaniline (2.3 mmol, 1 eq.) were dissolved in 9.6 mL pyridine, cooled to 0° C., treated with 292 μL ethyl sulfonyl chloride (3.1 mmol, 1.2 eq.) and stirred at 0° C. for 3 hours. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous layer was reextracted with ethyl acetate. The combined organic layers were dried, filtered and concentrated in vacuo to yield 1.6 g of the crude product, which was taken up in toluene and again concentrated in vacuo. The crude product was used in the subsequent transformations without further purification.
Reaction SMILES: C([NH:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[OH-].[K+].CO.Cl>O>[NH2:4][C:5]1[C:13]([CH3:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc(C(=O)O)c1N
Temperature: 80 °C
Yield: 75.6 %

Procedure:
A mixture of 0.45 g of 2-acetylamino-3-methyl-5-nitrobenzoic acid, 0.45 g of potassium hydroxide, 5 ml of methanol and 20 ml of water was heated to reflux at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water was poured into the mixture. The mixture was adjusted to pH 3 by an addition of 2N hydrochloric acid. A deposited precipitate was collected by filtration to obtain 0.28 g of 2-amino-3-methyl-5-nitrobenzoic acid of the formula:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([O:48]CC2C=CC=CC=2)[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCc3ccccc3)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O

Procedure:
2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (1.11 g, 1.41 mmol) was dissolved in ethyl acetate (45.0 ml)-THF (15.0 ml). Pd—C (222 mg) was added and the mixture was stirred at room temperature and for one hour in a hydrogen atmosphere. After completion of the reaction, the black solid was filtered off through celite, and the filtrate was concentrated under reduced pressure to give 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester as an amorphous (1.01 g, 100%).