Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:25])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Reactant: CCCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)n1cc(F)c(N(C)Cc2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a stirred solution of 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (0.200 g, 0.858 mmol) in CH2Cl2 (18 mL) were added N-pentyl chloroformate (0.142 g, 0.944 mmol) and Et3N (0.263 mL, 1.88 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred an additional 3 h. The crude reaction mixture was evaporated to dryness and the residue was triturated with methyl t-butyl ether (MTBE; 4×5 mL) to remove triethylamine hydrochloride. The combined organic layers were evaporated in vacuo. The crude product was purified by reverse phase chromatography. Pentyl 4-(benzyl(methyl)amino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (20.1 mg, 6.7%) was isolated as a yellow gum: 1H NMR (methanol-d4) δ 8.04 (d, J=6.2 Hz, 1H), 7.38-7.25 (m, 5H), 4.24 (t, J=6.6 Hz, 2H), 3.21 (d, J=3.3 Hz, 2H), 1.78-1.65 (m, 3H), 1.37 (dd, J=9.2, 5.5 Hz, 6H), 0.92 (t, J=7.1 Hz, 3H); ESIMS m/z 348 ([M+H]+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cccc(C#N)c1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (t, J=7.8 Hz, 1H), 7.94 (s, 1H), 8.04 (dt, J=7.8, 1.4 Hz, 1H), 8.25 (dt, J=8.1, 1.4 Hz, 1H), 8.42 (t, J=1.5 Hz, 1H), 9.32 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].CO.C(Cl)(Cl)Cl.[NH:31]([C:35]1[S:36][CH:37]=[C:38]([CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([NH2:46])[CH2:41]2)[N:39]=1)[C:32]([NH2:34])=[NH:33]>CO>[NH:31]([C:35]1[S:36][CH:37]=[C:38]([CH:40]2[CH2:45][CH2:44][CH2:43][CH:42]([NH:46][C:20]3[C:19](=[O:22])[C:18](=[O:23])[C:17]=3[NH:16][CH:12]3[CH2:13][CH2:14][CH2:15][CH:10]([C:8]4[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=4)[CH2:11]3)[CH2:41]2)[N:39]=1)[C:32]([NH2:34])=[NH:33]
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reactant: N=C(N)Nc1nc(C2CCCC(N)C2)cs1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N=C(N)Nc1nc(C2CCCC(Nc3c(NC4CCCC(c5csc(NC(=N)N)n5)C4)c(=O)c3=O)C2)cs1
Reaction time: 6 h

Procedure:
To a solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.1 g.) in 15 ml. of methanol/chloroform (50:50 v/v) was added a solution of 2-guanidino-4-(3-aminocyclohexyl)thiazole (0.07 g.) in methanol (3 ml.) and the resulting solution was allowed to stand at room temperature for 6 hours. After heating under reflux for 6 hours, the reaction mixture was concentrated and cooled to give, as a white amorphous solid, 1,2-bis[3-(2-guanidinothiazol-4-yl)cyclohexylamino]cyclobutene-3,4-dione. The carbon-13 magnetic resonance spectrum (δ relative to tetramethylsilane) in d6DMSO included one carbon singlets at 181.9, 175.0 167.0, 156.8, 155.4, 100.3, 52.4 and a series of signals from 52.4 to 24.1 (including resonances attributable to solvent) p.p.m.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:15][C:16]#[C:17][CH3:18])[C:12](O)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:27][OH:28]>>[OH:28][NH:27][C:12](=[O:13])[C:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])([CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:15][C:16]#[C:17][CH3:18]
Reactant: CC#CCC(Cc1cccnc1)(C(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NO
Agent: Cl
Product: CC#CCC(Cc1cccnc1)(C(=O)NO)S(=O)(=O)c1ccc(F)cc1
Yield: 45 %

Procedure:
2-(4-Fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl- hex-4-ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from 2-(4-fluoro-benzenesulfonyl)-2-pyridin-3-ylmethyl-hex-4-ynoic acid (0.29 g, 0.81 mmol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.15 g of the product was isolated. Yield 45%; white solid; mp 190° C.; MS: 377.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.60 (s, 3H), 2.70-3.00 (m, 2H), 3.53 (d, J=13.8 Hz, 1H), 3.74 (d, J=13.8 Hz, 1H), 7.50-7.58 (m, 2H), 7.80-7.95 (m, 3H), 8.35-8.40(m, 1H), 8.74-8.79 (m, 2H), 11.1 (brs, 1H); IR (KBr, cm−1): 3154m, 3105s, 3068s, 2875m, 1696s, 1630w, 1590s;
Reaction SMILES: Br[C:2]1[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=1[F:12].[CH2:13]([O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([O:17][C:18]1[CH:23]=[C:22]([C:2]2[C:8]([F:9])=[C:7]([F:10])[C:5]([NH2:6])=[C:4]([F:11])[C:3]=2[F:12])[CH:21]=[CH:20][CH:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1c(F)c(F)c(Br)c(F)c1F
Product: CCCCOc1cccc(-c2c(F)c(F)c(N)c(F)c2F)c1
Yield: 64.9 %

Procedure:
The title compound (250 mg) was prepared from 4-bromo-2,3,5,6-tetrafluoroaniline (300 mg, 1.23 mmol) and 3-butoxyphenylboronic acid (310 mg, 1.59 mmol) as a yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>O>[NH:20]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:21]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: NN
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A suspension of 2-bromo-5-(methanesulfonyl)-pyridine (7.3 g, 116 mmol), triethylamine (14.7 g, 145 mmol), and hydrazine hydrate (7.26 g, 145 mmol) in water (205 mL) was heated to 70° C. The reaction mixture became homogenous before the product started to precipitate out of this mixture (after 90 minutes). The reaction mixture was stirred at 70° C. for total of 5 hours and then was allowed to cool to room temperature and stirred for 18 hours. The precipitated product was collected by filtration, dried and recrystallized from hot ethanol to afford 2-hydrazinyl-5-(methanesulfonyl)-pyridine in 86% yield. Analytical data: 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 4.44 (br s, 2H), 6.80 (br d, J=8.7 Hz, 1H), 7.81 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 8.38 (d, 2.3 Hz, 1H), 8.57 (br s, 1H).
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19][CH3:20])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:21]O>C(O)(=O)C>[N:1]1([C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[S:19]([CH3:20])=[O:21])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)N2CCCC2)c(SC)cc1OC
Reactant: OO
Solvent: CC(=O)O
Product: COc1cc(NC(=O)N2CCCC2)c(S(C)=O)cc1OC

Procedure:
A reaction mixture containing 52 g. of N-pyrrolidinylcarbonyl-2-methylthio-4,5-dimethoxyaniline 19.8 ml. of 31 percent aqueous hydrogen peroxide and 1 l. of glacial acetic acid was stirred for about 20 hours at ambient temperature. The reaction mixture was then concentrated under reduced pressure to a residual wax. The residue was dissolved in 1 l. of methylene chloride and the methylene chloride layer washed twice with water and then dried. Removal of the methylene chloride in vacuo yielded a residue comprising N-pyrrolidinylcarbonyl-2-methylsulfinyl-4,5-dimethoxyaniline which, after recrystallization from a benzene-hexane solvent mixture, yielded material melting at 124°-7° C. (80 percent yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.Cl.[F:37][CH2:38][CH2:39][NH2:40].C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH2:38][F:37])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCCF
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCF)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A), 52 mg (0.519 mmol) of 2-fluoroethylamine hydrochloride and 67 mg (0.519 mmol) of N,N-diisopropylethylamine were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. Without further work-up, the reaction mixture was purified by preparative HPLC. 78 mg (yield: 53% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][C:41]4=[O:46])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C:41]1=[O:46])[CH:22]=2
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(2-oxopiperidin-1-yl)quinolin-3-yl]carbamate (0.004 g, 0.007 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 5 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H31N7O3 [M+H]+: m/z=490.3. found: 490.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: Cc1ccc(N=C=O)c(C)c1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)N(Cc2ccccc2)Cc2ccccc2)c(C)c1

Procedure:
A solution of 4.89 g. of 2,4-dimethylphenylisocyanate in 100 ml. of hexane is added to a solution of 5.32 g. of dibenzylamine in 150 ml. of hexane and the solution is stirred at room temperature for 2 hours and then evaporated. The residual solid is recrystallized from pentane to yield 1,1-dibenzyl-3-(2,4-dimethylphenyl)urea, m.p. 124°-126° C.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][CH2:13][C@H:14]([NH:21][C:22](=[O:44])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[CH:24]=1)[C:15](=[O:20])[NH:16][CH2:17][CH2:18][OH:19])(C)(C)C>>[OH:12][CH2:13][C@H:14]([NH:21][C:22](=[O:44])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25](/[CH:31]=[CH:32]/[C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:42])([F:43])[F:41])=[CH:35][CH:34]=2)[CH:24]=1)[C:15](=[O:20])[NH:16][CH2:17][CH2:18][OH:19]
Reactant: COc1ccc(C(=O)N[C@@H](COC(C)(C)C)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)N[C@@H](CO)C(=O)NCCO)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
Trifluoroacetic acid (1 mL) was added to 20 mg of N-[(S)-2-t-butoxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]-benzamide and the mixture was stirred for 20 minutes at room temperature. After removal of the solvent, the resulting residue was purified using a micromass spectrometer (ZMD produced by Micromass) equipped with a gradient high-performance liquid chromatograph 996-600E produced by Waters. The resulting solid was dried under reduced pressure to obtain 9 mg (57%) of N—[(S)-2-hydroxy-1-(2-hydroxyethylcarbamoyl)ethyl]-4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzamide.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=[CH:26][NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>>[CH:20]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][CH2:26][N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: C1=Cc2ccccc2-c2ccccc2N1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
As described for Example 2, 1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride, 1 mmol of 5H-dibenz[b,d]azepine and 2 mmol of triethylamine are stirred at room temperature for 5 hours to give the product as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:11])[C:4]([CH:6]1[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:5].CO.[BH4-].[Na+].Cl>>[OH:10][CH:8]1[CH2:9][CH:6]([C:4]([N:3]([O:2][CH3:1])[CH3:11])=[O:5])[CH2:7]1
Reactant: CON(C)C(=O)C1CC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CON(C)C(=O)C1CC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.6 %

Procedure:
N-Methoxy-N-methyl-3-oxocyclobutanecarboxamide (1 g, 0.006 mol) was dissolved in methanol (8 mL, 0.2 mol). To the mixture, sodium borohydride (0.2 g, 0.006 mol) was added. The reaction was stirred at rt for 1 h. To the reaction mixture was added 1N aq. HCl to adjust the pH to 2. The mixture was concentrated, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude product (1.4 g) as light yellow oil. LCMS calculated for C7H14NO3(M+H)+: 160.0; Found: 160.3.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Cl[CH:5]([CH:11]=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7]>CC(C)=O>[S:2]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][N:3]=[CH:1]1
Reactant: NC=S
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cncs1
Yield: 60 %

Procedure:
To a round bottom flask was added 250 mL of dry acetone, 7.5 g (0.123 mol) of thioformamide, and 18.54 g (0.123 mol) of ethyl 2-chloro-2-formylacetate. The reaction was heated at reflux for 2 hours. The solvent was removed in vacuo, and the residue was purified by chromatography (SiO2, 6 cm o.d. column, 100% CHCl3, Rf =0.25) to provide 11.6 g (60%) of the desired compound as a light yellow oil. NMR (CDCl3 δ1.39 (t, J=7 Hz, 3H), 4.38 (q, J=7 Hz, 2H), 8.50 (s, 1H), 8.95 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]([N:13]3[CH2:17][C@H:16]([NH:18][CH3:19])[C@@H:15]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=4)[CH2:14]3)=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:30]>>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([O:31][C:29](=[O:30])[N:18]([C@@H:16]2[C@@H:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:14][N:13]([C:11]([CH:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:12])[CH2:17]2)[CH3:19])=[CH:33][CH:34]=1
Reactant: CN[C@H]1CN(C(=O)C2CCN(CC3CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(OC(=O)Cl)cc1
Product: COc1ccc(OC(=O)N(C)[C@H]2CN(C(=O)C3CCN(CC4CC4)CC3)C[C@@H]2c2ccc(Cl)c(Cl)c2)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-[(3R,4S)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-methoxy-phenyl ester was prepared from rac-(1-cyclopropylmethyl-piperidin-4-yl)-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidin-1-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-methoxy-phenyl chloroformate instead of fluorophenyl chloroformate and was obtained as a colorless oil. MS m/e: 560.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:14]=[C:15]([CH3:23])[C:16]4[N:17]([C:19]([CH3:22])=[N:20][N:21]=4)[CH:18]=3)[C:11](=[O:24])[C:10](=O)[CH:9]2[C:26](=O)[CH2:27][CH3:28])=[CH:4][CH:3]=1.Cl.[CH:31]1([NH:34][NH2:35])[CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]3[C:26]([CH2:27][CH3:28])=[N:35][N:34]([CH:31]4[CH2:33][CH2:32]4)[C:10]=3[C:11](=[O:24])[N:12]2[C:13]2[CH:14]=[C:15]([CH3:23])[C:16]3[N:17]([C:19]([CH3:22])=[N:20][N:21]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: NNC1CC1
Agent: Cl
Product: CCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 68 using 5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-4-propionylpyrrolidine-2,3-dione (Step 70.1) and cyclopropylhydrazine hydrochloride. Further purification by preparative achiral SFC (4-ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) to afford the title product as colorless foam. tR: 1.02 min (LC-MS 2); ESI-MS: 447 [M+H]+ (LC-MS 2); Rf=0.36 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.6 Hz, 3H) 1.03-1.11 (m, 2H) 1.21-1.32 (m, 2H) 2.29 (dt, J=15.0, 7.6 Hz, 1H) 2.38 (dt, J=15.1, 7.7 Hz, 1H) 2.45 (s, 3H) 2.64 (s, 3H) 3.85 (tt, J=7.4, 3.8 Hz, 1H) 6.48 (s, 1H) 7.28-7.42 (m, 5H) 8.45 (s, 1H).
Reaction SMILES: [I:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].O>CC(N(C)C)=O>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C:5]2[C:6]([CH3:8])=[N:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Cc1nc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc(I)ccc1Oc1ccnc(Cl)c1
Temperature: 110 °C
Yield: 73.4 %

Procedure:
A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol), 2,4-dichloropyridine (8.56 g, 57.9 mmol) and K2CO3 (4.00 g, 28.9 mmol) in DMA (50 mL) was heated at 110° C. for 16 h under argon. The mixture was cooled to RT, treated with H2O, extracted with EtOAc (2×) and the combined organics were washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73%) as a white solid. MS (ESI) m/z: 346.9 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:14][CH:13]=3)O)=[C:8]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[S:7][C:6]=2[CH:35]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH2:10][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH:23]([CH3:27])[CH2:22]4)=[CH:16][CH:17]=3)=[C:8]([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=3)[S:7][C:6]=2[CH:35]=1
Reactant: CC1CCCN(CCOc2ccc(C(O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCN(CCOc2ccc(Cc3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.5 %

Procedure:
To a suspension of the product of Example 24 (0.466 g, 0.980 mmol) stirring in dichloromethane (24 mL) at 0° C. was added triethylsilane (0.94 mL, 5.8 mmol). After 10 minutes, trifluoroacetic acid (6.4 mL) was added at such a rate that the temperature was maintained below 5° C. The resulting solution was stirred at 0° C. for 2 hours, then quenched by pouring it into a saturated aqueous sodium bicarbonate solution (50 mL). Methanol was added as necessary to dissolve any residue. This mixture was then extracted with ethyl acetate (2×200 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification by radial chromatography (4 mm, silica gel, 8:2 ethyl acetate/methanol) gave 0.304 g (68%) of the title compound as a white foam: 1H NMR (300 MHz, MeOD-d4) δ7.26-7.30 (m, 3H), 7.18 (d, 1H, J=2.2 Hz), 7.03 (d, 2H, J=8.6 Hz), 6.74-6.83 (m, 5H), 4.07-4.11 (m, 4H), 3.00-3.20 (m, 4H), 2.80-2.85 (m, 1H), 2.35-2.41 (m, 2H), 2.05-2.18 (m, 1H), 1.43-1.48 (m, 1H), 1.06 (t, 3H, J=6.2 Hz); IR (KBr) 3385, 2958, 1677, 1610, 1509, 1239, 837 cm−1; MS (FD) m/z 460 (m+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1(C)C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(N2CCOCC2)CC1
Yield: 99.5 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) was dissolved in toluene (25 mL). Morpholine (2.186 mL, 25.09 mmol) was added and the reaction mixture was heated overnight in a atmosphere of argon in a Dean-Stark reflux apparatus. The mixture was allowed to reach room temperature and it was evaporated to dryness yielding tert-butyl 4-morpholino-5,6-dihydropyridine-1(2H)-carboxylate (6.70 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[C:7]([Cl:10])[CH:6]=[C:5]([SH:11])[C:3]=1[NH2:4].[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>ClCCl>[Cl:1][C:2]1[C:3]2[NH:4][C:12](=[O:13])[S:11][C:5]=2[CH:6]=[C:7]([Cl:10])[C:8]=1[CH3:9]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(Cl)cc(S)c(N)c1Cl
Solvent: ClCCl
Product: Cc1c(Cl)cc2sc(=O)[nH]c2c1Cl
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 2,4-dichloro-6-mercapto-3-methylaniline (2.08 g) in dichloromethane (40 ml) was added 1,1'-carbonyldiimidazole (1.78 g) at ambient temperature. The mixture was stirred for one hour at the same temperature. The separated precipitate was collected by filtration, washed with dichloromethane, and dried to give 4,6-dichloro-5-methyl-2-benzothiazolinone (1.40 g).