Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[C:13](C(O)=O)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[CH:3]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[C:18]([Cl:19])=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[CH:3]=1
Reactant: O=C(O)c1c2nc3cc(Cl)c(Br)cc3c-2[nH]c2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1cc2nc3cc4ccccc4[nH]c-3c2cc1Br
Yield: 94 %

Procedure:
7-Bromo-8-chloroquindoline-11-carboxylic acid from Example 74 (3.00 g, 7.99 mmol) was refluxed at 250° C. in diphenyl ether (30 mL) for 4 hours in an oversize flask. The mixture was cooled, diluted with petroleum ether (30 mL), and filtered. The filter cake was washed with petroleum ether (100 mL) and dried under high vacuum to yield 2.49 g (94%) of the title compound as a greenish solid, mp >246° C.; 1H NMR (DMSO-d6) δ 11.70 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.18 (d, J=8.4, 1H), 8.12 (d, J=8.4, 1H), 7.84 (s, 1H), 7.69 (t, J=6.8, 1H), 7.59 (t, J=7.2, 1H); 13C NMR (DMSO-d6) δ 143.65, 143.15, 133.39, 132.95, 128.65, 127.66, 127.97, 126.75, 125.51 (two signals), 121.53, 114.34, 113.10, 111.11; MS (EI, m/z) 331.9 (M+2+)
Reaction SMILES: [NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClC(Cl)Cl>[NH2:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH2:11][C@H:10]2[O:18][CH3:19])=[O:7])=[C:4]([O:23][CH3:24])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Reactant: CN(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNC(=O)N(C)C)C[C@H]1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a stirred and cooled solution (5° C.) of 3.99 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide in 90 parts of trichloromethane were added 1.32 parts of N,N-diethylethanamine. Then there was added dropwise a solution of 1.18 parts of dimethylcarbamic chloride in 60 parts of trichloromethane at a temperature below 5° C. Upon completion, stirring was continued first for one hour while cooling in an ice bath and further for 40 hours at room temperature. The reaction mixture was washed successively with water, sodium carbonate solution in water, and water, dried, filtered and evaporated. The product was filtered off and crystallized from acetonitrile, yielding 3.12 parts (73%) of cis-4-amino-5-chloro-N-[1-[2-[(dimethylamino)carbonylamino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 206.5° C. (compound 80).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[C:9][C:10]2[N:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1>C(OCC)(=O)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH:8]=[CH:9][C:10]2[N:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=4)[O:21][CH:22]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(C#CCCn4ccnn4)nn3)co2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ccc(C=CCCn4ccnn4)nn3)co2)cc1

Procedure:
3-(4-[1,2,3]Triazol-1-yl-but-1-ynyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine (0.047 g, 0.1 mmol) is dissolved in ethyl acetate (3 ml) and hydrogenated for 1 h at r.t. in the presence of palladium on charcoal (10%, 5 mg). After filtration and concentration in vacuo the residue yielded 3-(4-[1,2,3]triazol-1-yl-but-1-enyl)-6-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyridazine as an off-white solid. The raw product contained 60% product and 40% educt. The ratio was detected by HPLC-MS (High Performance Liquid Chromatography-Mass Spectrometry; Eluent: H2O/CH3CN, Gradient: in 20 minutes from 0% (volume to volume (v/v)) to 95% (v/v) CH3CN, UV-detection at 226 nm).
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([O:41][C:42]1[CH:47]=[CH:46][C:45]([C@@H:48]([OH:51])[CH2:49][NH2:50])=[CH:44][C:43]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54])C1C=CC=CC=1>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:50][CH2:49][C@H:48]([OH:51])[C:45]4[CH:46]=[CH:47][C:42]([OH:41])=[C:43]([NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:44]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)(=[O:17])=[O:18])=[CH:14][CH:15]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1OCc1ccccc1
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 225) and N-[2-benzyloxy-5-(2-amino-(1R)-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 8) according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.9 Hz, 3H), 1.20-1.80 (m, 10H), 1.95-2.15 (m, 2H), 2.50-3.30 (m, 7H), 2.97 (s, 3H), 3.55-3.70 (m, 2H), 4.70-4.85 (m, 1H), 5.90-6.10 (m, 1H), 6.48 (t, J=5.6 Hz, 1H), 6.83 (d, J=9.2 Hz, 2H), 6.90 (d, J=9.2 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.51 (d, J=9.2 Hz, 1H), 8.50-8.90 (brs, 1H), 9.39 (s, 1H), 9.61 (s, 1H); MS (ES) m/z: 703.4 (MH+); HRMS Calcd. for C33H47N6O7S2 (MH+): 703.2948. Found: 703.2946.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[OH-].[K+]>C(O)C.O>[Cl:26][C:4]1[CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][N:15]=3)[NH:10][CH:9]=2)[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2nccnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1cc(-c2c[nH]c3nccnc23)cc(Cl)n1
Temperature: 50 °C

Procedure:
A suspension of EXAMPLE 14A (0.300 g, 0.740 mmol) in ethanol (6 mL) was treated with a solution of potassium hydroxide (0.166 g, 2.96 mmol) in water (1.5 mL). The mixture was heated at 50° C. for 1.5 h. After cooling, the mixture was concentrated and 20% brine, sodium bicarbonate, and ethyl acetate were added. The suspension in both layers was filtered, washed with water, and dried to give the title compound. The organic layer in the filtrate was separated, dried, and concentrated. The residue was treated with ethyl acetate and diethyl ether, filtered, washed with diethyl ether, and dried to give additional title compound for a combined yield of 0.140 g (71%).
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[CH:7]=[CH:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20]C(=O)C(F)F)[O:16][C:15]3=[O:26])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:28][CH:29]([Cl:35])C(OCC)=O.C(N(CC)CC)C.[CH3:43][OH:44]>>[Cl:28][CH:29]([Cl:35])[C:43]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:26])[N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH:6]=[CH:7][S:2](=[O:27])(=[O:1])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[CH2:18]1)=[O:44]
Reactant: CO
Reactant: CCOC(=O)C(Cl)Cl
Reactant: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(F)F
Solvent: CCN(CC)CC
Product: O=C(NC[C@H]1CN(c2ccc(C3C=CS(=O)(=O)CC3)cc2)C(=O)O1)C(Cl)Cl
Yield: 75 %

Procedure:
The crude amine hydrochloride prepared in Step 1 of Example 15 (0.350 g, 0.975 mmol), ethyl dichloroacetate (0.60 ml, 4.88 mmol), and triethylamine (0.27 ml, 1.95 mmol) in methanol (5 mL) are stirred at r.t. overnight. The reaction mixture is evaporated to dryness and the residue purified by PTLC (10% methanol/dichloromethane) to give the title compound as white solid (0.32 g, 75%). M.p. 159-61° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20]1[N:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:33][CH:32]=2)[N:35]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 4-(trifluoromethyl)phenylhydrazine (CAS Reg. No. 368-90-1) to give the title compound as colorless solid. MS (ESI): m/z=528.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]1([S:16](Cl)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([S:16]([O:9][C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cccccc1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=c1cccccc1OS(=O)(=O)c1ccccc1
Yield: 76 %

Procedure:
2-Hydroxycyclohepta-2,4,6-trienone (0.2 g, 1.7 mmol) was reacted with benzenesulfonyl chloride (0.63 mL, 4.9 mmol) in 5 mL of pyridine to afford PZBG-4a in 76% yield (0.33 g, 1.3 mmol). 1H NMR (400 MHz, DMSO) δ=7.95 (d, J=7.6 Hz, 2H), 7.80 (t, J=7.6 Hz, 1H), 7.67 (t, J=8 Hz, 2H), 7.43-7.37 (m, 2H), 7.25 (t, J=8.4 Hz, 1H), 7.14-7.09 (m, 2H). 13C NMR (100 MHz, CDCl3) δ=179.24, 154.79, 141.19, 138.21, 136.37, 136.33, 135.57, 131.96, 130.92, 130.27, 128.76. ESI-MS(+): m/z 262.97 [M+H]+, 279.72 [M+NH4]+, 284.99 [M+Na]+.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:17]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(N2CCN(Cc3ccccc3)CC2)C1

Procedure:
4.90 g (21.1 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (120 ml) and, while stirring, 5.00 g (21.1 mmol) of tert-butyl 3-aminopiperidine-1-carboxylate hydrochloride and 14.2 g (169 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.99 g (75%) of yellow solid
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6](O)=O.C1C[O:22][CH2:21]C1>>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:6][CH2:21][OH:22]
Reactant: C1CCOC1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Product: COc1cc(CCO)c([N+](=O)[O-])c(OC)c1OC

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (5 g, 19.40 mmol) in THF (30 ml) was added by BH3 (1.0 M in THF, 29.1 ml) under nitrogen. The mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 3,4,5-Trimethoxy-2-nitrobenzyl methanol. The crude 3,4,5-trimethoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to PBr3 (2.40 ml, 25.22 mmol) in an ice bath. After 2 h, the mixture was extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:2) to afford B1 as a pale yellow oil, yield 68%. 1H NMR (500 MHz, CDCl3) δ 3.90 (s, 3H), 3.92 (s, 3H), 3.98 (s, 3H), 4.44 (s, 2H), 6.72 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:11][C:12](=[O:27])[NH:13][C:14]2[C:15]([CH3:26])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH3:10])=[CH:5][CH:4]=1)#[N:2].[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:22]3[CH:23]=[CH:24][C:19]([C:18]4[O:17][N:16]=[C:15]([CH3:26])[C:14]=4[NH:13][C:12]([O:11][C@@H:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH3:10])=[O:27])=[CH:20][CH:21]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccc(C#N)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)O[C@H](C)c4ccc(C#N)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(4-cyano-phenyl)-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[CH:2]12[CH2:20][CH:5]([CH:6]([NH:8][C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[NH:13][N:12]=3)=[O:10])[CH2:7]1)[CH2:4][NH:3]2.[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH:23]1([CH2:24][N:3]2[CH2:4][CH:5]3[CH2:20][CH:2]2[CH2:7][CH:6]3[NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH2:21][CH2:22]1
Reactant: N#CC(O)C1CC1
Reactant: O=C(NC1CC2CC1CN2)c1n[nH]c2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: O=C(NC1CC2CC1CN2CC1CC1)c1n[nH]c2ccccc12
Temperature: 25 °C
Yield: 50 %

Procedure:
To the suspension of N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indazole-3-carboxamide hydrochloride (0.36 mmol), cyclopropylcarboxaldehyde (0.9 mmol), and N,N-diisopropylethylamine (1.08 mmol), acetic acid (0.43 mmol) was added sodium triacetoxyborohydride (0.61 mmol). The reaction mixture was maintained at rt for 2 h and was poured into water, extracted with 95/5 dichloromethane/methanol (2×30 mL), and the combined extracts were concentrated. The residue was purified by preparative HPLC, thus providing the product in 50% yield. 1H NMR (CD3OD) δ 8.21 (m, 1H), 7.59 (m, 1H), 7.45 (m, 1H), 7.26 (m, 1H), 4.15 (m, 1H), 3.83 (m, 1H), 3.10 (m, 3H), 2.02 (m, 4H), 1.37 (m, 2H), 0.74 (m, 2H), 0.48 (m, 2H); LC/MS (EI) tR 2.72 min, m/z 311 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=O)[O:19]C1C=CC([N+]([O-])=O)=CC=1.Cl.Cl.[CH2:33]1[C:41]2[CH:40]=[CH:39][N:38]=[CH:37][C:36]=2[CH2:35][NH:34]1.C(C(C(C)C)(C(C)C)CN)(C)C.C(=O)([O-])N>ClCCl.CN(C)C=O>[CH2:33]1[C:41]2[CH:40]=[CH:39][N:38]=[CH:37][C:36]=2[CH2:35][N:34]1[C:18]([NH:1][C:2]1[N:7]=[N:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)=[O:19]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(N)nn1
Reactant: c1cc2c(cn1)CNC2
Agent: CC(C)C(CN)(C(C)C)C(C)C
Agent: Cl
Agent: NC(=O)[O-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Reaction time: 8 h

Procedure:
Methyl 6-aminopyridazine-3-carboxylate (2 g, 13.06 mmol) was suspended in dichloromethane (50 ml) followed by addition of dry pyridine (1.265 ml, 15.67 mmol) under nitrogen. To this suspension was added a dichloromethane solution of 4-nitrophenyl carbonochloridate (2.99 g, 14.37 mmol) via syringe at ambient temperature. The mixture was stirred overnight to give a suspension that was concentrated to half volume under a stream of nitrogen. 2,3-Dihydro-1H-pyrrolo[3,4-c]pyridine, dihydrochloride (2.52 g, 13.06 mmol) was dissolved in 30 ml dimethylformamide with triisopropylethylamine (6.84 ml, 39.2 mmol) and added to the carbamate mixture via syringe. After stirring the mixture overnight and removing most of the solvent under vacuum, water was added; and the resulting suspension was stirred for 30 minutes and filtered to give a solid which was washed with water. Flash chromatography of the dried solid gave the title compound.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].S(=O)(=O)(O)O.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>O.C(OCC)C>[NH2:2][C:1]([N:17]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:15][CH3:16])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: CCCNCCC
Reactant: N#C[C-](C#N)C#N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCCN(CCC)C(N)=C(C#N)C#N
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
In the manner of Example VI, part C, 25 g of potassium tricyanomethanide in 75 ml of water and 100 ml of diethyl ether were treated with 19 g of concentrated sulfuric acid to give an ether solution of HN=C=C(CN)2. The ether solution was treated with 19.6 g of dipropylamine and the mixture allowed to stand for 1/2 hour. The ether was removed by distillation under reduced pressure and the residue heated to 150°. To the hot residue were added 500 ml of aqueous ethanol and the mixture was boiled vigorously for 15 minutes. The mixture was again concentrated and the residue heated at 150° for about 16 hours. The mixture was dissolved in aqueous ethanol, treated with activated charcoal and chilled for two days at about 5°. The separated solid was collected by filtration and dried to give 31 g of 3-amino-2-cyano-3-(dipropylamino)propenenitrile, m.p. 100°-105° from toluene. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:37][CH2:36][CH:33]4[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCC2CCNCC2)CC1
Temperature: 50 °C
Yield: 15.2 %

Procedure:
4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared in Example 10b) was dissolved in 330 μL of t-butanol along with 4-piperadine methanol (38 mg, 0.33 mmol). Then, 330 μL of 1.0 M potassium t-butoxide in t-butanol was added. The reaction mixture was heated to 50° C. overnight. The reaction was quenched with the addition of a few drops of trifluoroacetic acid and the solution was diluted to 2 mL in volume with methanol. The reaction mixture was purified by reverse phase HPLC to give 9 mg of the product as a white solid. 1H NMR DMSO-d6) δ 9.37 (s, 1H), 8.25 (s, 2H), 7.62 (s, 1H), 4.28 (d, 2H), 3.63 (m, 4H), 3.54 (m, 4H), 3.08 (d, 2H), 2.59 (t, 2H), 1.93 (m, 1H), 1.71 (d, 2H), 1.29 (qd, 2H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C@@H:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C@H:9]1[C:16]([O-:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C@@H:19]1([NH3+:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC2CCCC2C1C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2CCC[C@@H]2[C@H]1C(=O)[O-]
Product: [NH3+][C@H]1CCCc2ccccc21
Temperature: 23.5 °C
Reaction time: 3.5 h

Procedure:
The ethyl acetate solution of racemic N-t-butyloxycarbonyl-3-azabicyclo[3.3.0]octane-2-carboxylic acid from Example 2, Method 2, was added to a solution of (S)-1,2,3,4-tetrahydro-1-naphthylamine (56.7 g, 0.385 mol) in ethyl acetate (300 mL). The mixture was stirred for 3-4 hours at 22-25° C., then filtered, and the solids washed with ethyl acetate (200 mL). The product was dried at 20-30° C. under vacuum for 4 hours to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.N1C=CC=CC=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(Cl)n2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a 20 mL scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 0.207 g, 1.131 mmol) and pyridine (2.84 ml, 35.1 mmol) and the solution was cooled to 0° C. To the yellow solution was added 4-(trifluoromethoxy)benzoyl chloride (0.508 g, 2.262 mmol) to give an orange suspension. The reaction mixture was stirred for one hour, quenched by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure in the presence of silica gel. The silica-adsorbed material was then purified by silica gel chromatography (25-75% ethyl acetate/hexanes gradient) to afford the desired compound N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(trifluoromethoxy)benzamide 14A as an orange solid (215 mg, 51% yield); ESI-MS: m/z 370.0 (M+H)+.