Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: NCCSC(=O)N1CCCCC1

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (300 mg) and piperidine (184 μl) were subjected to similar reations to those described in References 2 and 4 to give 2-piperidinocarbonylthioethylamine (crude formate: 137 mg). The product was dissolved in anhydrous methanol (3 ml). To the solution were added triethylamine (432 μl) and mitomycin A (151 mg: 0.7 molar equivalent). The solution was treated in a similar manner to that described in Example 1 to obtain Compound 42 (0.21 mg) in the form of grayish blue powders with a yield of 74%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH:27]([CH3:29])[NH:26][CH2:25][CH2:24]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)[CH:20]=[CH:21][CH:22]=4)[CH:27]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(-c3ccco3)c21
Product: CC1c2c(cccc2-c2ccco2)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:7]([N:5]1[CH:6]=[C:2]([NH:1][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=[CH:4]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
To a solution of 4-amino-1-tritylimidazole (0.30 g, 0.92 mmol) in dichloromethane (4 ml) were added sequentially triethylamine (0.19 ml, 1.37 mmol) and benzoyl chloride (0.13 ml, 1.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes, then diluted with dichloromethane and washed sequentially with water, saturated aq. NaHCO3 solution, water and saturated brine. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane 0:100 to 10:90) to yield the title compound as an orange solid (0.36 g, 92%); MS (ISP): 430.3 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:14]=[C:15]([C:20](O)([CH3:22])[CH3:21])[CH:16]=[C:17]([CH3:19])[CH:18]=2)[CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([C:20]([CH3:22])=[CH2:21])[CH:14]=2)[CH3:11])=[CH:24][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(CN(C)Cc2ccc(C(C)(C)C)cc2)cc(C(C)(C)O)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(C)c1cc(C)cc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Yield: 31.6 %

Procedure:
Compound 86 (0.40 g; 1.18 mmol) was dissolved in pyridine (20 ml). While the solution was stirred in an ice bath, phosphorus oxychloride (1.81 g; 11.8 mmol) was added dropwise. After completion of the addition, the mixture was removed from the ice bath, and stirred for 30 minutes at room temperature, followed by heating under reflux for 4 hours. The mixture was brought to room temperature, and poured into ice+saturated aqueous sodium bicarbonate solution. The mixture was neutralized with sodium bicarbonate, and extracted with chloroform (70 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to thereby yield 0.12 g of the target compound (yield: 31.6%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[CH:13]3[OH:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(#N)C>[CH2:23]([NH:27][C:28]([O:22][CH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:20](=[O:21])[N:12]1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[N:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:29])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN=C=O
Reactant: O=C1c2cccnc2C(O)N1c1ccc2ccc(Cl)nc2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC(=O)OC1c2ncccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reaction time: 3 h

Procedure:
A suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-hydroxy-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (1 g.) in acetonitrile (100 cc.) containing n-butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) is heated at the reflux temperature for 1 hour 30 minutes. n-Butyl isocyanate (7.25 cc.) and triethylamine (0.5 cc.) are then added and heating at the reflux temperature is continued for a further 3 hours. The solution is filtered and the filtrate is concentrated under reduced pressure (40 mm.Hg). The residue obtained is triturated with diisopropyl ether (20 cc.). The solid is filtered off and is recrystallised from acetonitrile (35 cc.) to give 7-n-butylaminocarbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.96 g.) melting at 215° C.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1>>[O:37]=[S:34]1(=[O:38])[CH2:35][CH2:36][N:31]([C:2]2[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][C:15]([F:21])=[CH:16][CH:17]=4)[N:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[F:28])[CH:11]=3)=[O:7])=[CH:4][N:3]=2)[CH2:32][CH2:33]1
Reactant: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(Cl)nc1
Reactant: O=S1(=O)CCNCC1
Product: O=C(NCc1cn(-c2ccccc2F)c2cc(F)ccc2c1=O)c1ccc(N2CCS(=O)(=O)CC2)nc1

Procedure:
6-(1,1-Dioxo-1-thiomorpholin-4-yl)-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-ylmethyl]-nicotinamide was prepared starting from 6-chloro-N-[7-fluoro-1-(2-fluoro-phenyl)-4-oxo-1,4-dihydro-quinolin-3-yl-methyl]-nicotinamide (example I-105) and thiomorpholine-1,1-dioxide. MS calcd. for C26H22F2N4O4S [(M+H)+] 525.1, obsd. 525.2.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+:15]>CO>[OH:1][CH:2]([CH2:11][CH2:12][OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[Na+:15]
Reactant: COC(=O)CCCCC(O)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCCCC(O)CCO

Procedure:
Methyl 6,8-dihydroxyoctanoate (0.15 g, 0.80 mmol; containing about 10% of the 6,7-isomer) was dissolved in 3 mL of methanol and 1.00 M sodium hydroxide in methanol (0.80 mL, 0.80 mmol) was added. The solution was stirred under reflux for 3 hr. The solvent was evaporated in vacuo yielding 0.15 g of sodium 6,8-dihydroxyoctanoate as a white powder. Yield was quantitative.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a solution of 6-Amino hexanoic acid (50 grams, 379.65 mmol) in 1N Sodium hydroxide (95.3 ml) is cooled to 5 to 10° C. and simultaneously added from two separating funnels 4N Sodium hydroxide (190.6 ml) and Benzyl chloroformate (50% in Toluene, 196 grams) keeping the temperature at 5 to 10° C., later stirred at the same temperature for 2 hours and allowed to room temperature and stirred overnight. The reaction mixture is washed with Diisopropyl ether (3×200 ml), cooled to 10° C.; pH adjusted to 2 with dilute HCl, residue precipitated is filtered, dried and slurried in Diisopropyl ether to give pure 6-Benzyloxycarbonylamino hexanoic acid (38 grams) as white powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)#[N:26].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>CN(C=O)C>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:33]([C:29]2[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=2)[C:25]#[N:26])(=[O:35])=[O:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(S(=O)(=O)n2cc(Cl)c3c4c(ccc32)OCCNC4)c1
Temperature: 50 °C

Procedure:
tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added. The mixture was stirred for 10 minutes at room temperature before 3-cyanobenzene-1-sulfonyl chloride (13 mg, 0.062 mmol) was added. The reaction mixture was stirred for 20 minutes before TFA (2 mL) was added and the mixture was heated at 50° C. overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as an off-white solid (1.3 mg) in the form of the trifluoroacetate salt. MS m/z 388 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]=[C:10]=S)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:9][C:10]2[O:31][C@:23]3([CH2:22][N:21]=2)[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]3)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: S=C=Nc1ncc(Cl)cc1Cl
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1cnc(NC2=NC[C@@]3(CN4CCC3CC4)O2)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
To 3,5-dichloro-2-isothiocyanatopyridine (0.11 g, 0.55 mmol) in N,N-dimethylformamide (10 mL) was added Et3N (0.17 mL, 1.21 mmol) and (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.13 g, 0.56 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (10 mL) and N,N′-diisopropylcarbodiimide (0.26 mL, 1.65 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)—N-(3,5-dichloropyridin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.08 g, 0.24 mmol, 44% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 8.91 (s, 1H), 8.11-8.17 (m, 1H), 7.97 (d, J=2.44 Hz, 1H), 3.84 (d, J=9.77 Hz, 1H), 3.59 (d, J=9.77 Hz, 1H), 2.95-3.04 (m, 2H), 2.72-2.81 (m, 2H), 2.66 (t, J=7.63 Hz, 2H), 2.01 (s, 1H), 1.89 (s, 1H), 1.54-1.62 (m, 2H), 1.42-1.50 (m, 1H). MS (LC/MS) R.T.=0.78; [M+]+=326.1.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[C:6]2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Clc1cccc(CBr)c1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3cccc(Cl)c3)c12
Yield: 86 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 3-chlorobenzyl bromide as starting materials, the title compound was obtained in a yield of 86% as an oil.
Reaction SMILES: [Br:1][CH:2]([Br:6])[C:3]([OH:5])=[O:4].O[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[Br:1][CH:2]([Br:6])[C:3]([O:5][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13])=[O:4]
Reactant: O=C(O)C(Br)Br
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(ON1C(=O)c2ccccc2C1=O)C(Br)Br

Procedure:
Dibromoacetic acid (0.1 mmole) and N-hydroxyphthalimide (0.1 mmole) are mixed and coupled in THF in the presence of DCC for 2 hours. The product, (N-dibromoacetoxyphthalimide) is isolated by filtration and dried. Radical-induced dehalogenation (0.1 mmole scale) using the general method with tributyltin deuteride furnished the N-deuterioacetoxyphthalimide with two atoms of deuterium. The N-ditritioacetoxyphthalimide can be prepared the same way.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]([C:27]3[O:28][C:29](=[O:43])[C:30]4[C:35]([C:36]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:26])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([O:17][Si](C(C)(C)C)(C)C)[CH:16]=3)[C:3]=12.[ClH:44]>CCO>[ClH:44].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:25]([C:27]3[O:28][C:29](=[O:43])[C:30]4[C:35]([C:36]=3[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH3:26])[N:9]=[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[C:15]([OH:17])[CH:16]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O[Si](C)(C)C(C)(C)C)c2)c2c(N)ncnc21
Agent: Cl
Solvent: CCO
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cncc(O)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
3-(1-(4-amino-3-(5-((tert-butyldimethylsilyl)oxy)pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one single enantiomer (intermediate S.3, second eluted enantiomer under the conditions described above, 0.077 g, 0.130 mmol) was dissolved in a solution of HCl 1 M in EtOH (0.417 ml) and the mixture was stirred at RT for 5 hrs. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel cartridge (DCM to DCM:MeOH=95:5) to afford title compound as a white solid (0.034 g, 0.066 mmol, 51% yield). This compound proved to be the first eluted enantiomer under Chiral HPLC conditions of Method A9: Rt=13.2 min, ee=95.6%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:27]1[C:29]2([CH2:34][CH2:33][NH:32][CH2:31][C@H:30]2[OH:35])[CH2:28]1>>[OH:35][C@@H:30]1[CH2:31][N:32]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)[CH2:10][CH2:9]2)[CH2:3][O:2][CH3:1])[CH2:33][CH2:34][C:29]21[CH2:28][CH2:27]2
Reactant: COC[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 58 %

Procedure:
In analogy to the procedure described in example 1K, (S)-4-methoxy-3-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyraldehyde and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 58% yield as light yellow foam. MS: 470.2 (MH+).
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[F:11][C:10]1[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[N:3][C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: NC(=O)c1cc(F)c(N2CCCCC2)nc1Nc1ccc(F)cc1
Temperature: 100 °C
Yield: 85.5 %

Procedure:
A solution of 6-chloro-5-fluoro-2-(4-fluorophenylamino)nicotinamide (50 mg, 0.176 mmol) and piperidine (1 mL, 10.12 mmol) was sealed in a small microwave vial and heated in a heating block at 100° C. for 2 hrs. The reaction mixture was diluted with CH2Cl2 and washed with bicarbonate and water. The reaction mixture was concentrated and the dark crude material was chromatographed (ISCO Companion 40 g silica gel column and eluted with (90:9:1 CH2Cl2:MeOH: NH4OH)t/CH2Cl2 gradient (20-100%)) to give 50 mg of 5-fluoro-2-(4-fluorophenylamino)-6-(piperidin-1-yl)nicotinamide as a brown solid. LCMS: (M+H)+=333.21. 1H NMR (400 MHz, CDCl3) δ ppm 10.68 (1H, s), 7.52-7.57 (2 H, m), 7.22 (1H, d, J=14.06 Hz), 6.94-7.00 (2H, m), 5.47 (2H, br. s.), 3.64 (4H, d, J=6.15 Hz), 1.62-1.72 (6H, m).
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+:2]=[N-:3].[H-].[K+].[CH2:25]([N:27]([CH2:30][CH2:31]Cl)[CH2:28][CH3:29])[CH3:26]>CN(C)C=O.C(OCC)(=O)C>[N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([O:22][CH2:26][CH2:25][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Reactant: CCN(CC)CCCl
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOC1=C(C(=O)OCc2ccccc2)N2C(=O)C(N=[N+]=[N-])C2C1
Temperature: 0 °C

Procedure:
An ice-cold solution of benzyl 6-azido-1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (1 mmol) in anhydrous dimethylformamide (1 ml) is added dropwise to an ice-cold mixture of potassium hydride (1 mmol) in anhydrous dimethylformamide (4 ml). After stirring for several minutes in the cold and under nitrogen, the mixture is treated with diethylaminoethyl chloride and stirred in the cold for 2 hr. The mixture is diluted with ethyl acetate, washed thoroughly with water and brine, dried over magnesium sulfate, and filtered. Evaporation of the solvent in vacuo gives benzyl 6-azido-3-(2-diethylaminoethyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH2:8](OC(Cl)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[CH2:8]([O:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2][Br:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)CCCBr
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCBr)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.9 %

Procedure:
To an ice cold solution of 5 g of 4-bromobutyric acid and 5.5 g of benzylchloroformate in 100 mL of dichloromethane was added 5 mL of triethylamine and then 700 mg of 4-dimethylaminopyridine. A vigorous exothermic reaction ensued with evolution of carbon dioxide. After stirring for 3 h, the mixture was diluted with 100 mL of dichloromethane and washed with 200 mL of saturated sodium bicarbonate, dried over magnesium sulfate, and concentrated to an oil. Azeotropic drying with toluene gave 8 g of 4-bromobutyric acid benzyl ester as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](C2C=CC(O)=C([N+]([O-])=O)C=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:27]([O-])=O.C(O)C.O.NN.[H][H]>[Ni].O>[NH2:27][C:3]1[CH:4]=[C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: O=[N+]([O-])c1cc(C(c2ccc(O)c([N+](=O)[O-])c2)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C(C(F)(F)F)C(F)(F)F)ccc1O

Procedure:
30 parts by weight 2,2-bis (4-hydroxy-3-nitrophenyl)-1,1,1,3,3,3-hexafluoropropane are suspended in a mixture of 240 parts by weight ethanol and 120 parts by weight water. 1.5 parts by weight Raney nickel and two times 18.5 parts by weight hydrazine hydrate are added to the suspension, and subsequently, the mixture is heated for the reflux. After the development of hydrogen has abated at the end of about 4 hours, suction is applied to remove the Raney nickel and the ethanol/water mixture is removed in a vacuum. The residue is taken up with about 400 parts by weight of diluted hydrochloric acid and optionally filtered off from insoluble components. After the addition of sodium acetate and sodium carbonate, the 2,2-bis (3-amino-4- hydroxy phenyl)-1,1,1,3,3,3-hexafluoropropane is precipitated; the yield is approximately 66%. Analysis (reported/found) revealed the following data: C 49.2%/49.0%; H 3.3%/3.4%; N 7.7%/7.5%; F 31.1%/31.0%; 1H-NMR in d6 -DMSO: δ (ppm)=9.2 (2H,s,OH), 6.6 (6H, m,aromatic), 4.6 (4 H, s, --NH2).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 28 mg, 0.09 mmol) in dichloromethane (2 ml), at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) and then methanesulfonylchloride (25 μl, 37 mg, 0.32 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (18 mg, 52%).
Reaction SMILES: C(O)(C(F)(F)F)=O.O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>>[N:27]1([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:26])[N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:11]=2)[CH:31]=[N:30][CH:29]=[N:28]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: c1nc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(Cn2cncn2)cc1)c1ccccc1
Yield: 27 %

Procedure:
The title compound was prepared as its TFA salt in 27% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 1,2,4-triazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.34 (s, 2H), 7.15 (br d, 2H), 7.26–7.43 (m, 7H), 8.10 (s, 1H), 8.38 (s, 1H); HPLC-MS: m/z=309.1 (M+1); Rt=2.74 min.