Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([NH:33][CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@H:27]1[C@@H:32]([N:33]([C:17](=[O:19])[CH2:16][C:11]2[NH:10][C:9]3[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=3[S:13](=[O:14])(=[O:15])[N:12]=2)[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[C@H:31]2[CH2:39][C@@H:28]1[CH2:29][CH2:30]2)=[O:26])[CH3:23]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.216 g, 0.649 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.164 g, 0.649 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.681 mmol). Then N-methylmorpholine (0.138 g, 1.36 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 4 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C25H36N4O7S2 568.2, found 569.5 [M+H+].
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[CH:33][N:32]=[C:31]([C:35]([N:37]2[C:45]3[C:40](=[CH:41][C:42]([F:46])=[CH:43][CH:44]=3)[CH:39]=[CH:38]2)=[O:36])[CH:30]=1>CN(C=O)C>[F:46][C:42]1[CH:41]=[C:40]2[C:45](=[CH:44][CH:43]=1)[N:37]([C:35]([C:31]1[N:32]=[CH:33][N:34]=[C:29]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:30]=1)=[O:36])[CH:38]=[CH:39]2
Reactant: O=C(c1cc(Cl)ncn1)n1ccc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)n1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75.0 mg (0.26 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one dihydrochloride and 150 μL (0.87 mmol) DIPEA were added to 70 mg (0.25 mmol) (6-chloropyrimidin-4-yl)-(5-fluoroindol-1-yl)-methanone in 5 mL DMF. The reaction mixture was stirred overnight at RT and then evaporated down i. vac. The residue was taken up in 20 mL water and stirred for 10 min. The precipitate was suction filtered, dissolved in 2.5 mL DMF and purified by preparative HPLC. The product fractions were combined and concentrated by rotary evaporation using the rotary evaporator.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:29]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH:30]=3)[CH:14]=2)([N:10]=[N+]=[N-])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:37]([OH:40])(=[O:39])[CH3:38]>C1COCC1.[Zn]>[C:37]([OH:40])(=[O:39])[CH3:38].[C:1]([N:4]1[CH2:5][CH2:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[NH:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=3)=[O:21])=[C:15]([C:29]3[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH:30]=3)[CH:14]=2)([NH2:10])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N=[N+]=[N-])(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N1CCC(N)(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [4-(1-acetyl-4-azido-piperidin-4-yl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 40.0 mg, 0.0822 mmol) and zinc (54.0 mg, 0.822 mmol) in 1.6 mL of THF was added acetic acid (0.40 mL). The resulting mixture was stirred at RT for 16 h under Ar. The solid was removed by filtration on Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (10% MeOH/DCM) to give 13 mg (30%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.33 (d, 1H, J=8.6 Hz), 7.91 (s, 1H), 7.52 (dd, 1H, J=8.6, 2.3 Hz), 7.40 (s, 1H), 5.77 (m, 1H), 3.76-3.98 (m, 2H), 3.42 (m, 2H), 2.46 (m, 2H), 2.32 (m, 2H), 2.13 (s, 3H), 2.07 (m, 2H), 1.86-2.03 (m, 2H), 1.93 (s, 6H), 1.59 (t, 2H, J=6.1 Hz). Mass spectrum (ESI-neg, m/z): Calcd. for C26H32N6O2, 459.3 (M−H). found 459.5.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.C([O:24][B:25](OCC)[O:26]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:18]1[C:19]2[C:15](=[CH:14][C:13]([B:25]([OH:26])[OH:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: Brc1ccc2c(c1)CCC2
Reactant: CCOB(OCC)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g, 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallised from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][NH:15][C:14](=[O:20])[CH:13]=2)[CH:5]=1.[CH3:21][C:22]([CH3:44])([CH3:43])[CH2:23][CH:24](OS(C(F)(F)F)(=O)=O)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C1COCC1>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[C:17]([O:18][CH3:19])=[CH:16][N:15]([CH:24]([CH2:23][C:22]([CH3:44])([CH3:43])[CH3:21])[C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:14](=[O:20])[CH:13]=2)[CH:5]=1
Reactant: CC(C)(C)CC(OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cn(C(CC(C)(C)C)C(=O)OCc2ccccc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A little at a time, 41.8 mg (1.04 mmol) of sodium hydride (60% in mineral oil) were added to a suspension of 261 mg (purity 87%, 870 μmol) of 4-chloro-2-(5-methoxy-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile in 10 ml of THF, and the mixture was stirred at RT for another 1 h. 481 mg (1.31 mmol) of benzyl 4,4-dimethyl-2-{[(trifluoromethyl)sulphonyl]oxy}pentanoate (racemate) as a solution in 3 ml of THF were quickly added dropwise to the resulting reaction solution, and after the addition had ended the mixture was stirred at RT for another 1.5 h. The reaction was terminated by addition of 10 ml of saturated aqueous ammonium chloride solution and 15 ml of methyl tert-butyl ether. The phases were separated and the aqueous phase was extracted three times with 10 ml of methyl tert-butyl ether. The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (80 g silica cartridge, 60 ml/min, cyclohexane/ethyl acetate gradient). Yield: 294 mg (71% of theory)
Reaction SMILES: COC(=O)C1C=CC(C([NH:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([Br:18])[C:12]=2[CH3:19])=O)=C(F)C=1.[C:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[Br:18][C:13]1[C:12]([CH3:19])=[C:11]([NH:10][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)[CH:16]=[C:15]([F:17])[CH:14]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Product: Cc1c(Br)cc(F)cc1NC(=O)c1ccc(C(C)(C)C)cc1

Procedure:
Intermediate 37 was prepared analogue to Intermediate 34 by replacing Intermediate 33 with 4-tert-butyl-benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:27]=[CH:26][N:25]([CH:28]([CH3:30])[CH3:29])[N:24]=1>CN(C=O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][C:23]2[CH:27]=[CH:26][N:25]([CH:28]([CH3:30])[CH3:29])[N:24]=2)[N:3]=1
Reactant: CC(C)n1ccc(CCl)n1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc(Cn2nc(Br)c3c([N+](=O)[O-])cccc32)n1
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
To a solution of 3-bromo-4-nitro-1H-indazole (Preparation B; 2.2 g, 9.1 mmol) in DMF (18 mL) was added potassium carbonate (2.5 g, 18 mmol) at ambient temperature. After 15 minutes, at ambient temperature, 3-(chloromethyl)-1-isopropyl-1H-pyrazole hydrochloride (1.8 g, 9.1 mmol) was added. The mixture was allowed to stir for 18 hours. The mixture was concentrated, diluted with ice-water and stirred for one hour. The resulting fine solids were collected by filtration and dried under vacuum to give 3-bromo-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-4-nitro-1H-indazole (3 g, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](I)[CH:9]=2)=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[C:19]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([CH3:14])[N:11]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(I)n1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-methyl-pyridine (example A.29) (1.5 g, 5 mmol) and commercially available 3-bromo-benzene-boronic acid (1.005 g, 5 mmol) according to the general procedure IVb. Obtained as a white solid (0.15 g, 8.4%). MS (ISP) 358.0 [(M+H)+], 360.0 [(M+2+H)+] and 362.2 [(M+4+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.F[C:14]1[CH:27]=[CH:26][C:17]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:22][CH:21]=1)(=[O:19])[C:17]1[CH:26]=[CH:27][CH:14]=[CH:15][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Yield: 26.2 %

Procedure:
A solution of N-(4-pyridyl)piperazine (815 mg), 4-fluorobenzophenone (1.2 g) and powdered potassium carbonate (912 mg) was stirred at 95° C. in DMSO (10 ml) overnight. The solution was poured into water (150 ml) and extracted with dichloromethane (3×50 ml). The dichloromethane extracts were combined, washed with water, dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (ICN Alumina N 32-63) using 1% methanol in dichloromethane as eluant to give a solid. The solid was recrystallised from a mixture of ethyl acetate/isohexane to give 1-(4-benzoylphenyl)-4-(4-pyridyl)piperazine (450 mg) as a solid. m.p.136-137° C.
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:33][CH:34]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1

Procedure:
A solution of 1-(4-nitrobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (22.4 mg, 0.047 mmol) in EtOH (3 mL) was hydrogenated at 1 atm for 1 h in the presence of 5% palladium on charcoal (10 mg) at 25° C. The catalyst was removed by filtration and washed with EtOH (5 mL). The combined filtrate was evaporated to afford 1-(4 aminobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (compound No. 516) as a pale yellow solid (20.1 mg, 96%). The purity was determined by RPLC/MS (99%); ESI/MS m/e 449.1 (M++H, C23H27F3N4O2).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([C:11]([O:13]C)=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH3:15]>CO>[N:1]1[C:10]2[CH:9]([C:11]([NH2:15])=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCCc2cccnc21
Reactant: N
Solvent: CO
Product: NC(=O)C1CCCc2cccnc21
Temperature: 100 °C

Procedure:
Methyl 5,6,7,8-tetrahydroquinoline-8-carboxylate (9 g.) was dissolved in methanol previously saturated with ammonia (270 ml.) and heated in a bomb at 100° C. for 5 days. The solvent was removed and the residual oil triturated with hot petroleum ether (40°-60°). The resultant solid was filtered and then recrystallised from ethyl acetate giving the title compound as colourless needles mpt. 132° C. (5 g.). Found: C, 67.7; H, 7.1; N, 16.0% C10H12N2O requires: C, 68.1; H, 6.9; N, 15.9%.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[N:6]=[N:5]1>C(O)C.[Pd]>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[N:5]1
Reactant: CC(C)(C)Cn1nnc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)Cn1nnc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2,2-Dimethylpropyl)-5-nitro-1H-1,2,3-benzotriazole (4.46 g, 19.04 mmol, 1.0 equiv.) was dissolved in ethanol (50 ml), flushed with nitrogen, and charged with 10% Pd/C (2.026 g, 1.904 mmol, 0.1 equiv.). After sparging with nitrogen, the mixture was sparged with hydrogen (1 atm) and stirred at ambient temperature for 5 hours. The mixture was filtered through Celite, the residue was washed with methanol and the filtrate was concentrated in vacuo, providing the titled compound. LRMS m/z (M+H) 205.0 found, 205.3 required.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(C)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-tert-butyl-benzenesulfonamide [CAS 608523-94-0] according to general procedure II. Light yellow solid. MS (ISP) 584.1 [(M−H−]; mp 232° C.
Reaction SMILES: CS(O[CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)(=O)=O.[Na].[NH2:15][C:16]1[NH:20][N:19]=[N:18][N:17]=1>CN(C=O)C>[NH2:15][C:16]1[N:17]=[N:18][N:19]([CH:6]2[CH:11]3[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]3)[CH2:7]2)[N:20]=1
Reactant: Nc1nnn[nH]1
Reactant: CS(=O)(=O)OC1CN2CCC1CC2
Agent: [Na]
Solvent: CN(C)C=O
Product: Nc1nnn(C2CN3CCC2CC3)n1

Procedure:
3-Methanesulphonyloxy-1-azabicylo[2.2.2]octane (D8) (2.0 g, 9.7 mmol) and the sodium salt of 5-aminotetrazole (D15) (2.5 g, 2.0 eq) were dissolved in dry DMF (50 ml) and the reaction carried out as for Example 10. The product (E11) isolated from column chromatography was a white crystalline solid (124 mg, 6.6%), which was recrystallised from ether, m.p. 132-134° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([N:19]=[N+]=[N-])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 149.4 %

Procedure:
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (350 mg), from the synthesis of Example 17 (analogous to 10f), was dissolved in MeOH (5 mL) prior to the addition of 5% Pd/BaSO4 (300 mg). A hydrogen balloon was added and the mixture was stirred. After stirring 1 h, the Pd/BaSO4 was filtered off and the solvent was concentrated to give {(3S)-1-[(1S,2R,4R)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (497 mg). MS found: (M−H)−=496.5. (18b) A portion of the above material (341 mg) was dissolved in dichloroethane (5 mL) prior to the adddition of acetone (0.25 mL) and NaBH(OAc)3 (436 mg). After 2 h, the solution was concentrated. The resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried, filtered, and concentrated. The resulting residue was dissolved in MeOH (2 mL) prior to the addition of 37% formaldehyde in water (0.1 mL). After 15 min, NaBH3CN (111 mg) was added. After 2 h, saturated NaHCO3 was added and some of the MeOH was removed. EtOAc was added and the organic layer was dried, filtered, and concentrated. This material was passed through a plug of silica and concentrated. This material (300 mg) was dissolved in CH2Cl2 (5 mL) prior to the addition of TFA (2.5 mL). After 30 min, it was concentrated and dried. A portion of the resulting residue (35 mg) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.02 mL) and 3-trifluoromethylphenyl isocyanate (0.013 mL). After 2 h, the solution was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (7 mg). MS found: (M+H)+=641.3.
Reaction SMILES: O.FC(F)(F)C(O)=[O:5].[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[C:22]([NH2:24])=[O:23])=[CH:19][CH:18]=[C:17]([C:25]#[CH:26])[CH:16]=2)=[O:11].[OH-].[Na+]>O1CCOCC1>[C:25]([C:17]1[CH:16]=[C:15]2[C:20]([C:21]([C:22]([NH2:24])=[O:23])=[C:13]([NH:12][C:10]([NH2:9])=[O:11])[NH:14]2)=[CH:19][CH:18]=1)(=[O:5])[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: C#Cc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
Water (6 μl L, 0.25 mmol) and trifluoroacetic acid (150 μL, 2.0 mmol) were added to a solution of 2-aminocarbonylamino-6-ethynylindole-3-carboxamide (Compound 10-1, 20 mg, 0.083 mmol) in 1,4-dioxane (2 mL), the mixture was stirred at 95° C. for 5 hours. 1 N Sodium hydroxide aqueous solution (2 mL) was added to the reaction mixture under ice-cooling, and the whole was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (10 mL), and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resultant solid was washed with diethyl ether (2 mL) and dried under reduced pressure to give the title compound (12 mg) as a colorless solid (yield 57%).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3]I.C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:21])[CH:15]=1.O>CN(C)C=O>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:16]([Cl:21])[CH:15]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
2,2,2-Trifluoroethyliodide (15.2 g) and potassium carbonate (10.0 g) were added to a solution of 4-bromo-2-chlorophenol (5.0 g) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 80° C. for 20 hours. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give 4-bromo-2-chloro-1-(2,2,2-trifluoroethoxy)benzene as a colorless oil (3.0 g, 43%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[F:19]>CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17]#[N:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]=1[F:19]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Cl)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)Cc1ccc(Cl)c(F)c1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
A solution NaBH4 (15 mg, 0.39 mmol) in EtOH (4 mL) was cannulated into a mixture of the ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanoacrylate (200 mg, 0.79 mmol) in EtOH (2 mL) at room temperature. After 5 minutes, the mixture was quenched with 0.1N HCl, concentrated in vacuo, diluted with H2O, extracted with DCM, dried over MgSO4, concentrated and subject to flash chromatography (SiO2 with DCM) to give ethyl 3-(4-chloro-3-fluorophenyl)-2-cyanopropanoate (0.20 g, 58%). LCMS (APCI+) [M+H]+254.3.