Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:14]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.Cl>C(O)C>[O:17]=[C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:15][C:14]1[N:13]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:3][C:2]2=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2c3c(nn2-c2ccccc2)c(=O)[nH]c2ccccc23)CC1
Agent: Cl
Solvent: CCO
Product: O=C(Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12)N1CCNCC1
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 4-[(4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetyl]piperazine-1-carboxylate, 4 mL of 6 N aqueous hydrochloric acid, and 12 mL of ethanol was heated at 60° C. for 5 hours. The mixture was allowed to cool to ambient temperature and was concentrated under reduced pressure. The residue was triturated with acetonitrile, isolated by filtration, and dried to afford 1.60 g of 1-(2-oxo-2-piperazin-1-ylethyl)-2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one; hydrochloride as a white solid.
Reaction SMILES: ClCCl.[C:4](=O)([O:32]C1C=CC([N+]([O-])=O)=CC=1)[O:5][CH2:6][C:7]1[C:8]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[N:9][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:11][CH:12]=1.CN1CCOCC1.[CH2:50]([NH2:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CCCCCC>[CH2:50]([NH:57][C:4](=[O:32])[O:5][CH2:6][C:7]1[C:8]([CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[N:9][C:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[CH:11][CH:12]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(OCc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)OCc1ccc(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.4 %

Procedure:
To a dichloromethane (1 ml) solution of [6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methylpyridin-3-yl]methyl 4-nitrophenyl carbonate (51 mg, 0.089 mmol) were added N-methylmorpholine (0.020 ml, 0.18 mmol) and benzylamine (0.012 ml, 0.11 mmol) sequentially at 0° C. The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the eluate of hexane:ethyl acetate=4:1 was concentrated under reduced pressure. The solid thus obtained was washed with diisopropyl ether and collected by filtration to give the title compound (33 mg, 0.060 mmol, 68%) as a white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[CH3:36][C:37]1[CH:42]=[C:41]([C:43]([N:45]2[CH2:54][C:53]3[CH:52]=[N:51][N:50]([CH3:55])[C:49]=3[NH:48][C:47]3[CH:56]=[CH:57][CH:58]=[CH:59][C:46]2=3)=[O:44])[CH:40]=[CH:39][C:38]=1[CH2:60][CH2:61][C:62](O)=[O:63].CCN(C(C)C)C(C)C>ClCCl>[O:25]1[CH2:29][CH2:28][O:27][CH:26]1[CH:30]1[CH2:35][CH2:34][N:33]([C:62](=[O:63])[CH2:61][CH2:60][C:38]2[CH:39]=[CH:40][C:41]([C:43]([N:45]3[CH2:54][C:53]4[CH:52]=[N:51][N:50]([CH3:55])[C:49]=4[NH:48][C:47]4[CH:56]=[CH:57][CH:58]=[CH:59][C:46]3=4)=[O:44])=[CH:42][C:37]=2[CH3:36])[CH2:32][CH2:31]1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Reactant: C1CC(C2OCCO2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCC(C2OCCO2)CC1
Yield: 83 %

Procedure:
HBTU (327 mg, 0.86 mmol) was added to a solution of 4-[1,3]dioxolan-2-yl-piperidine from Example E33 (143 mg, 0.91 mmol) and 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (320 mg, 0.82 mmol) in dichloromethane (20 ml) and DIEA (0.7 ml, 4.02 mmol) and the mixture was stirred for 20 h at room temperature. Dichloromethane was added and the solution was washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 4% methanol:96% dichloro-methane to 8% methanol:92% dichloromethane) to give a white solid identified as the title compound (359 mg, 83%).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=1[F:31])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[C:24]=1[F:31]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccc(F)c(F)c3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1ccc(F)c(F)c1F

Procedure:
The 2-trifluoroacetamido-3-(2,3,4-trifluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (8.43 g, 18.2 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 5.82 g. (87%). EA, MS(FD).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([C:4]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
A mixture of ethyl isonipecotate (65 mmol; 10.2 g), anhydrous potassium carbonate (195 mmol; 26.9 g) and benzyl bromide (78 mmol; 13.36 g) in anhydrous N,N-dimethylformamide (100 ml) was stirred at 70° C. for 18 hours. After cooling, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (3×200 ml). The combined organic phases were washed with saturated NaCl solution (3×100 ml), dried over sodium sulfate and evaporated under reduced pressure. A crude product was obtained, which was purified on a column of alumina (eluting with chloroform) to give 13.84 g (86%) of pure product as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:15]=1[O:23][CH3:24])(=[O:13])=[O:12])[C:6](=[O:25])[C:5]2([N:35]1[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:36]1[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34].O>C(O)(=O)C.[Fe]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[C:5]([N:35]3[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:36]3[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])[C:6]2=[O:25])(=[O:12])=[O:13])=[C:15]([O:23][CH3:24])[CH:16]=1
Reactant: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2OC)c2ccc(Cl)cc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)N(S(=O)(=O)c2ccc(N)cc2OC)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A suspension of 450 mg of the compound obtained in Example 185 and 381 mg of iron in acetic acid (5 ml) was stirred at 80° C. for one hour. Water was added to the solution and the resulting mixture was extracted with EtOAc; the organic layer was washed with a saturated aqueous solution of NaHCO3 and with saturated brine, dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=20/1 to 10/1; v/v) to obtain 301 mg of the title compound (amorphous).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([Li])CCC>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:15]=[C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 152 %

Procedure:
7-Nitro-1-tetralone (1.00 g, 5.23 mmol) was dissolved in dry THF (5 mL) and added to a solution of methyltriphenylphosphonium bromide (2.00 g, 5.60 mmol) and n-butyllithium (2.5 M in hexanes, 2.2 mL, 5.5 mmol) in THF (10 mL) cooled by an ice water bath. The mixture was allowed to warm to room temperature and stirred overnight. It was poured into ice water (45 mL) and extracted with EtOAc (3×20 mL). The extract was washed with NaCl solution, dried (MgSO4), filtered and concentrated to give a black solid (1.504 g). It was dissolved in CHCl3 and flash chromatographed over silica gel (65 g) eluting with EtOAc/hexane (1:20) to afford a white solid (263 mg, 27% yield): mp 45-47° C.
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[C:4]([NH2:8])[N:5]([NH2:7])[NH2:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Na+:13]>CC(C)=O.C(#N)C>[C:9]([O-:12])(=[O:11])[CH3:10].[NH2:2][NH+:3]=[C:4]([NH2:8])[N:5]([NH2:7])[NH2:6].[Cl-:1].[Na+:13]
Reactant: NN=C(N)N(N)N
Reactant: Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Product: N[NH+]=C(N)N(N)N
Product: [Cl-]

Procedure:
Triaminoguanidinium acetate is synthesized by reacting triaminoguanidine hydrochloride and sodium acetate in acetone or acetonitrile. Sodium chloride is produced as a byproduct of the reaction and is removed, producing the triaminoguanidinium acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)n(C)n1
Reactant: NCC(F)(F)F
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NCC(F)(F)F)n(C)n1
Yield: 64 %

Procedure:
As described for example 122, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using 2,2,2-trifluoroethylamine instead of isopropylamine, to the title compound (30 mg, 64%) which was obtained as a white solid. MS: m/e=409.0 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:13]COC)[CH:5]=1)([CH3:3])[CH3:2].[C:17](Cl)(=O)C.Cl.C[Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO.CCCCCC>[CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:17])=[O:9])=[C:6]([OH:13])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: COC(=O)c1ccc(C(C)C)cc1O
Reaction time: 2 h

Procedure:
The 4-isopropyl-2-methoxymethoxybenzoic acid (5.3 g, 23.6 mmol) was dissolved in methylene chloride (75 mL) and MeOH (75 mL). Acetyl chloride (1 mL) was added to generate HCl. The reaction mixture was stirred for 2 h. The reaction was washed with water (2×150 mL), dried (MgSO4), and concentrated under vacuum. The crude product was dissolved in methylene chloride (100 mL) and MeOH (30 mL), and to this solution a 2 M hexane solution of trimethylsilyldiazomethane (11.8 mL, 23.6 mmol) was added dropwise. After 1 h, the solvent was removed under vacuum, giving the title compound as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[N:7][O:6][N:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25]>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:3]([C:4]2[C:8]([NH:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[N:7][O:6][N:5]=2)=[N:2][OH:1])=[CH:19][C:18]=1[C:24]([F:25])([F:26])[F:27]
Reactant: COCCCNc1nonc1C(Cl)=NO
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: COCCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 87 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step F, using N-hydroxy-4-[(3-methoxypropyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride and 4-fluoro-3-(trifluoromethyl)benzeneamine as the starting materials in 87% yield. LCMS for C14H16F4N5O3 (M+H)+: m/z=378.1. 1H NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 9.05 (s, 1H), 7.30 (dd, J=10.0, 9.6 Hz, 1H), 7.13-7.11 (m, 1H), 7.05-7.00 (m, 1H), 6.22 (t, J=5.7 Hz, 1H), 3.35-3.32 (m, 2H), 3.25-3.19 (m, 5H), 1.79-1.72 (m, 2H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]([CH3:16])=[CH:4][CH:3]=1.[F:17]C1C=CC(C(O)=O)=C(I)C=1C>>[F:17][C:4]1[CH:3]=[CH:2][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:5]=1[CH3:16]
Reactant: Cc1c(F)ccc(C(=O)O)c1I
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Product: Cc1c(F)ccc(C(=O)O)c1-n1nccn1

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 4-fluoro-2-iodo-3-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:17][C:18]([O:20]C)=[O:19])[C:5]1=[O:22])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[CH:1]([N:4]1[C:8](=[O:9])[C:7]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]([CH2:17][C:18]([OH:20])=[O:19])[C:5]1=[O:22])([CH3:3])[CH3:2]
Reactant: COC(=O)CN1C(=O)N(C(C)C)C(=O)C1(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1C(=O)N(CC(=O)O)C(C)(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl (3-isopropyl-5-methyl-2,4-dioxo-5-phenylimidazolin-1-yl)acetate, isomer B from Step B (700 mg, 2.3 mmol) in MeOH (20 mL) was added 1 N aqueous NaOH (5.0 mL, 5.0 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The reaction was quenched by addition of 1 N HCl (5 mL) and the reaction was poured into water (100 mL) and the mixture was adjusted to pH 3 with 1 N HCl. The aqueous mixture was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound. MS: m/z=291 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[CH3:12][N:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[CH:4]2)[C:20]([NH:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: O=C=Nc1cccnc1
Reactant: CNc1ccc2c(ccn2C)c1
Product: CN(C(=O)Nc1cccnc1)c1ccc2c(ccn2C)c1
Yield: 45 %

Procedure:
The title compound was prepared from 1-methyl-5-methylamino-1H-indole (D15) and 3-pyridyl isocyanate (D4) using a procedure similar to that described for Example 2 Method B. The crude produce was obtained in 45% yield.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]([OH:12])=O)[CH2:5][CH2:4]1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:6]1[CH2:5][CH2:4][CH:3]([CH3:2])[CH2:8][CH2:7]1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC1CCN(CC(=O)O)CC1
Agent: Cl
Product: CC1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 46.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-methylpiperidin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 130, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-methylpiperidin-1-yl)acetamido)propanamide (19.2 mg, 46.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.21 (s, 1H), 7.94 (d, 1H), 7.60 (d, 2H), 7.29-7.33 (m, 5H), 7.19-7.27 (m, 2H), 6.98-7.04 (m, 4H), 4.67-4.71 (m, 1H), 4.52 (s, 2H), 3.68-0.80 (m, 2H), 2.94 (d, 2H), 2.77-2.90 (m, 2H), 2.00-2.06 (m, 2H), 1.54-1.60 (m, 2H), 1.30-1.33 (m, 1H), 1.13-1.19 (m, 2H), 0.89 (d, 3H). MS (EI) for C30H34FN3O4. found 520.6 (MH+).
Reaction SMILES: [CH3:1][NH:2][OH:3].[H-].[Na+].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20]Cl)=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1>CN(C)C=O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH2:20][N:2]([CH3:1])[OH:3])=[N:18][N:19]=[C:15]3[CH2:14][N:13]=[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:11]=2[CH:28]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CNO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(O)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N-methylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(S(C)(=O)=O)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared following Example 46, was reacted with 2,4-dimethoxypyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 131. NMR (CDCl3): 1.96-2.04 (2H, m), 2.18-2.26 (4H, m), 2.84-2.91 (1H, m), 2.86 (3H, s, Me), 3.12-3.20 (2H, m), 3.82 (2H, s, CH2), 3.84-3.90 (4H, m, CH2), 3.98-4.02 (4H, m, CH2), 4.04 (3H, s, Me), 4.08 (3H, s, Me), 7.32 (1H, s, Ar) and 8.94 (1H, s, Ar). MS: (ESI+): MH+=535.39
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1>>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:21][CH:22]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 72 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine) was combined with N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide to yield N-((1R,2R)-2-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (117 mg, 72% yield) as a white powder. 1H-NMR (CDCl3) δ 7.91 (s, 1H), 7.24 (m, 2H), 7.05 (d, J=8.0 Hz, 1H), 6.84 (br s, 1H), 5.37 (m, 1H), 3.87 (m, 1H), 3.23 (q, J=18.6, 9.2 Hz, 3H), 2.83 (m, 6H), 2.69 (m, 2H), 2.20 (br s, 2H), 2.07 (br s, 2H), 1.82 (br s, 2H), 1.35 (br s, 6H). LC/MS (ESI+)=561 (M+H). MP=122° C. dec.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:6][S:5]2.[OH-].[NH4+:15]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:15])(=[O:12])=[O:11])[CH:7]=[CH:6][S:5]2
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)c1c(Cl)nc2sccn12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.7 %

Procedure:
2 g (1 mol equiv.) 6-Chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride was dissolved in 20 mL acetonitrile and cooled to 0° C. Dropwise, 3.7 mL (3 mol equiv.) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min, during which a white precipitate was formed. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo affording 1.62 g (88%) 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J=4.6 1H), 7.98 (d, J=4.6 Hz, 1H), 8.00 (br.s., 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].Cl[CH2:13][CH2:14][C:15]([N:18]=CC1C=CC=CC=1)([CH3:17])[CH3:16]>>[NH2:18][C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: CC(C)(CCCl)N=Cc1ccccc1
Reactant: O=C1CCc2ccccc2N1
Product: CC(C)(N)CCN1C(=O)CCc2ccccc21

Procedure:
Prepared analogously to the method described for Example 6a) from 15.7 g (107 mmol) of 3,4-dihydroquinolin-2-one and 24.9 g (119 mmol) of (3-chloro-1,1-dimethylpropyl)-(1-phenylmethylidene)amine. Unlike in the method mentioned above, the product is precipitated not as the maleate but as the hydrochloride. Yield: 6.9 g (24%, hydrochloride); melting range: 200° C.-203° C.