Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][C@@H:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:35][C@@H:10]1[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][C@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Product: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
(3R*,5S*)-1-(tert-Butoxycarbonyl)-5-(methoxycarbonyl)piperidine-3-carboxylic acid (575 mg) was suspended in toluene (10 ml), diphenylphosphoryl azide (0.52 ml) and triethylamine (0.34 ml) were added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, benzyl alcohol (0.52 ml) and triethylamine (0.34 ml) were added and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was washed with water, 5% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:4) was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 ml), 10% palladium-carbon (50% containing water) (70 mg) was added, and the mixture was subjected to catalytic reduction at ambient temperature under a hydrogen atmosphere (1 atm) for 12 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the object compound (370 mg) as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH:19]([CH3:20])[CH3:21])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
N-Tert-butoxycarbonyl-D-valine benzyl ester (70.7 g, 0.23 mol) was dissolved in a mixture of trifluoroacetic acid and methylene chloride (150 mL in 1:4 ratio) and the reaction mixture was heated at 50-60° C. After 6 h, the reaction mixture was concentrated to give D-valine benzyl ester trifluoroacetic acid salt (156.8 g) as a viscous oil which was converted to the free amine just prior to use.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][CH2:14][C:15]([NH:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>ClCCl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1

Procedure:
A solution of tert-butyl 3-(2-(6-(trifluoromethyl)quinazolin-4-ylamino)acetamido)azetidine-1-carboxylate (prepared as described in Example 1, Step F) (1 g, 2.35 mmol, 1.00 equiv) in dichloromethane (10 mL) and TFA (25% in DCM, 1 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under vacuum, and the title compound was obtained as a white solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])([CH3:28])([CH3:27])[CH3:26]>C(O)C>[C:25]([O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Cc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A mixture of 7-Benzyl-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (20 mg, 0.06 mmole) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (22 mg, 0.12 mmole) in anhydrous ethanol (0.6 ml) was stirred at 130° C. in a CEM microwave synthesizer for one hour before it was cooled to room temperature, concentrated and purified by flash column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a white solid (22 mg). LC-MS ESI+: 460 (M+1)+; ESI−: 458 (M−1)−.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:20][CH2:19]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: NC1CC1
Product: N#Cc1c(NC2CC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 217 mg (3.80 mmol) of cyclopropylamine to give 44 mg (43% of theory) of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:21]([Cl:22])=[C:20]([Cl:23])[C:10]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+]>C(O)C>[Cl:22][C:21]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:11][C:10]=2[C:20]=1[Cl:23]
Reactant: CCOC(=O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc2cc(-c3ccccc3)sc2c(Cl)c1Cl
Yield: 94.2 %

Procedure:
A mixture of 4.47 g of ethyl[(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetate and 150 ml of 95% ethanol was treated with 150 ml of 20% sodium hydroxide solution. The mixture is refluxed for 3 hours and concentrated in vacuo to remove ethanol. Acidificaton at 0°-10°, followed by ether extraction, yields 3.9 g of [(6,7-dichloro-2-phenylbenzo[b]thien-5-yl)oxy]acetic acid as white needles, mp 209°-211°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][C:12]1[C:16]([CH2:17][OH:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1.C(N(CC)CC)C>ClCCl>[I:11][C:12]1[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:13]=1
Reactant: OCc1cn(C2CCCCO2)nc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1cn(C2CCCCO2)nc1I
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and. To a stirred solution of oxalyl chloride (18.576 g, 146.35 mmol, 3.01 equiv) in anhydrous dichloromethane (300 mL) maintained under nitrogen at −78° C. was added DMSO (15.138 g, 193.75 mmol, 3.98 equiv) dropwise. The reaction mixture was stirred at −65° C. for 30 min. A solution of (3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl)methanol (15.0 g, 48.68 mmol, 1.00 equiv) in dichloromethane (100 mL) was then added dropwise at −65° C. and the reaction was stirred for another 60 min at −65° C. Triethylamine (40.6 mL) was added dropwise at −65° C. and the reaction was stirred for 30 min at −65° C. The reaction was warmed to 0° C. then quenched by the addition of 100 mL of saturated NH4Cl solution. The resulting mixture was extracted with 3×400 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:20) to give 13.48 g (90%) of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde as a golden oil. 1H NMR (300 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.57 (s, 1H), 5.49 (dd, J=2.7 Hz, 9.9 Hz, 1H), 3.95-3.91 (m, 1H), 3.68-3.62 (m, 1H), 2.11-2.01 (m, 3H), 1.69-1.62 (m, 3H) ppm. LCMS (method A, ESI): RT=1.35 min, m/z=307.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][S:26][C:22]=4[C:21](=[O:27])[N:20]4[CH2:28][CH2:29][C@H:19]4[C:18]=23)[N:10]=1>CN(C)C=O>[N:1]1([CH2:8][C:9]2[O:13][N:12]=[C:11]([C:14]3[N:15]=[CH:16][N:17]4[C:23]5[CH:24]=[CH:25][S:26][C:22]=5[C:21](=[O:27])[N:20]5[CH2:28][CH2:29][C@H:19]5[C:18]=34)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C1c2sccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: O=C1c2sccc2-n2cnc(-c3noc(CN4CCCCC4)n3)c2[C@@H]2CCN12
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
0.34 ml (3.45 mmol) of piperidine was added to a suspension of 400 mg (1.15 mmol) of (S)-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]-imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 12 hours. The solution was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous solution was extracted with methylene chloride and the organic phases were dried, filtered and evaporated. The residue was chromatographed (silica gel, methyl acetate/methanol 15:1). There were obtained 375 mg (82%) of (S)-1-(5-piperidin-1-ylmethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H, 10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e]-[1,4]diazepin-8-one as a colourless foam, Rf=0.22 (silica gel, methyl acetate/methanol 15:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21].BrC1C=[C:27]2[C:32](=CC=1)[NH:31][C:30](=O)[C:29](OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:31]([CH2:32][CH3:27])[CH2:30][CH3:29])[C:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[C:20]([F:23])([F:22])[F:21]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Reactant: FC(F)(F)c1c(Oc2ccccc2)c(Cl)nc2ccc(Br)cc12
Product: CCN(CC)c1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccccc1
Temperature: 100 °C

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-phenoxy-4-(trifluoromethyl)quinoline (Intermediate 8, step b) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 100° C. under reflux condenser for 2.5 hours.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].[C:11](Cl)(=[O:13])[CH3:12]>>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][C:11](=[O:13])[CH3:12])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CC(N)(C1)C2
Reactant: CC(=O)Cl
Product: CC(=O)NC12CC(OC(C)=O)(C1)C2

Procedure:
The commercially available 3-aminobicyclo[1.1.1]pentane-1-carboxylic acid can be converted to the methyl ketone intermediate by treatment with either methyl lithium or methylmagnesium bromide (Scheme 2). Baeyer-Villagar type oxidation with mCPBA or other peroxycarboxylic acids can give 3-aminobicyclo[1.1.1]pentan-1-yl acetate. The amine can then be coupled with an appropriate carboxylic acid or acid chloride, such as acetyl chloride to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3). Selective hydrolysis of the ester group with hydroxide ion gives N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1). Alternatively, starting with the commercially available 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid and carrying out a Curtius reaction or modified Curtius reaction using diphenylphosphoryl azide gives the amino alcohol intermediate, which can then be treated with acetyl chloride (1 eq.) in the presence of base (for example, K2CO3, Na2CO3, NaHCO3, TEA, and the like) to give N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) or with acetyl chloride (>2 eq.) in the presence of base (for example, K2CO3, Na2CO3, NaHCO3, TEA, and the like) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:26])[CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: O=C(O)C(F)(F)F
Reactant: COCCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Product: COCCCN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
H2O2 (70%, 2.5 mL, ca. 50 mmol) was added dropwise to a stirred solution of TFM (7.1 mL, 50 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 32 (1.7 g, 5.0 mmol) and TFA (1.9 mL, 25 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 33 (620 mg, 35%) as a red solid: mp 129-131° C.; 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.39 (br s, 1H, NH), 3.57-3.66 (m, 2H, NCH2), 3.46 (t, J=6.3 Hz, 2H, OCH2), 3.33 (s, 3H, OCH3), 3.11 (dt, J=7.4, 0.9 Hz, 2H, H-8), 3.06 (dt, J=7.4, 1.1 Hz, 2H, H-6), 2.68 (t, J=6.0 Hz, 2H, NCH2), 2.52 (t, J=7.2 Hz, 2H, NCH2), 2.28 (s, 3H, NCH3), 2.20 (p, J=7.4 Hz, 2H, H-7), 1.77 (tt, J=7.2, 6.4 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.7, 58.6, 55.8, 54.3, 41.7, 38.8, 33.4, 32.4, 27.4, 25.6; MS (APCI) m/z 348 (MH+, 100%). Anal. calcd for C17H25N5O3: C, 58.8; H, 7.3; N, 20.2. Found: C, 58.8; H, 7.0; N, 20.0%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]2)=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:50][S:51]([O:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[C:5]([C:16]#[N:17])[CH:4]=[C:3]([NH:18][C:19]3[N:24]=[C:23]([N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[C:22]4=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]4[N:20]=3)[C:2]=2[Cl:1])[CH2:9]1)(=[O:53])=[O:52]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(CO)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(COS(C)(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask charged with (+/−)-2-((2-chloro-5-cyano-3-(2-(hydroxymethyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (0.05 g, 0.085 mmol) in THF (0.427 ml) was added triethylamine (0.036 ml, 0.256 mmol) and methanesulfonyl chloride (9.97 μl, 0.128 mmol). The reaction mixture was stirred at room temperature 2 h. The reaction mixture was poured into a separatory funnel containing 1:1 saturated aqueous sodium bicarbonate: ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (4-(2-Chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl methanesulfonate was isolated as a pale yellow solid and used as is for further chemistry.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:15][C@@H:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1.Cl>C(O)C.[Pd]>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@@H:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](C)NC(=O)c1cccc2c1NC1CCCC21
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A solution of ethyl (2S)-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (8.4 mmol, 2.5 g) in ethanol (40 mL) was added to a mixture of 5% palladium on carbon (2 g) in ethanol (2 mL). Concentrated hydrochloric acid (10 mL) was added and the resulting mixture was hydrogenated at 45 psi for 4 hours. The reaction mixture was filtered through Celite. The filter bed was washed well with ethanol and the combined filtrates were concentrated. The resulting oil was partitioned between 1 N NaOH and ethyl acetate. The orgainc phase was dried over MgSO4, filtered and concentrated to yield an oil (1.9 g, 6.1 mmol, 73%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:28][CH2:29][CH2:30][C:31]#[N:32].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([NH:32][CH2:31][CH2:30][C:29]#[N:28])=[O:26])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: N#CCCN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)c2cc(OCC(=O)NCCC#N)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), 3-aminopropionitrile (12 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (23 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH:10](C(O)=O)[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].O>Cl.CO>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][NH:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C1NCCc2c1[nH]c1cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Yield: 79 %

Procedure:
7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylic acid (5 g, 21.36 mmol) was suspended in 130 ml of 3N HCl in a 500 ml round-bottom flask and refluxed overnight (16 hr) with stirring. Upon cooling, a light brown solid precipitated out, which was collected by filtration and washed with H2O. The salt obtained by filtration above was then dissolved in hot methanol (200 ml) and treated with 3M K2CO3 (5-10 ml) such that the pH is around 9. 100 ml of H2O was added to this mixture, which was then allowed to stir at RT. The methanol was evaporated on a rotary evaporator to give a white aqueous suspension of the desired free base, which was collected by filtration (3.2 g, 79% yield). 1H-NMR (300 MHz, methanol-d4): δ 2.73 (t, 2H), 3.11 (t, 2H), 3.94 (s, 2H), 6.73 (m, 1H), 6.94 (m, 1H), 7.30 (dd, 1H). Retention Time (LC, method: ammonium acetate standard): 1.25 min. MS (M+H+): 191.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:3][C:4]=1[CH2:9][CH3:10]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: CCc1cc(Br)ccc1Cl
Product: CCc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-ethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 329.2 [M+H]+) was prepared from 4-bromo-1-chloro-2-ethylbenzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH2:14][O:15][CH3:16])([CH3:3])[CH3:2].[NH2:17][C:18](=[N:36]O)[C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=1)[CH2:22][N:23]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:24]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:36]=[C:18]([C:19]3[CH:20]=[C:21]([CH:33]=[CH:34][CH:35]=3)[CH2:22][N:23]([CH3:24])[CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[N:17]=2)=[CH:7][C:6]=1[CH2:14][O:15][CH3:16])([CH3:2])[CH3:3]
Reactant: COCc1cc(C(=O)O)ccc1OC(C)C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Product: COCc1cc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1OC(C)C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 56 (201.83 mg; 0.90 mmol) and Intermediate 51 (220 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a slightly yellow solid. 1H NMR (CDCl3) δ 8.25 (d, J=2.2 Hz, 1H), 8.12 (d, J=1.7 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 8.06 (br s, 1H), 7.57-7.55 (m, 1H), 7.47 (t, J=7.5 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 4.70 (quint., J=6.1 Hz, 1H), 4.54 (s, 2H), 3.78 (s, 2H), 3.50 (s, 3H), 3.23 (s, 2H), 2.41 (s, 3H), 1.50 (s, 9H), 1.40 (d, J=6.0 Hz, 6H). HPLC (Method A) Rt 4.96 min (Purity: 100.0%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[CH2:16]1[C:19]2([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH2:18][O:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]3([CH2:16][O:17][CH2:18]3)[CH2:20]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: C1CNCC2(C1)COC2
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCCC4(COC4)C3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 2-oxa-6-azaspiro[3.5]nonane by following the similar procedure as described for intermediate-11a.