Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:28]12([N:38]=[C:39]=[O:40])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>O1CCCC1.C1CCCCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)([CH2:12][C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1)[C:39]([NH:38][C:28]12[CH2:37][CH:32]3[CH2:31][CH:30]([CH2:36][CH:34]([CH2:33]3)[CH2:35]1)[CH2:29]2)=[O:40]
Reactant: COC(=O)C(Cc1ccncc1)Cc1ccncc1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-pyridin4-yl-2-pyridin4-ylmethyl-propionic acid methyl ester (24.44 g, 95 mmol) in tetrahydrofuran (300 ml) chilled with a dry ice/acetone bath, lithium diisopropylamide (70 ml of a 1.5M solution in cyclohexane, 105 mmol of lithium diisopropylamide) was added dropwise over 15 minutes. After stirring for 20 minutes, the solution temperature was elevated to -40° C. After 30 minutes of stirring at -40° C., a solution of adamantyl isocyanate (16.92 g, 95 mmol) in tetrahydrofuran (100 ml) was added dropwise over 10 minutes. After 15 minutes stirring, the cooling bath was removed and the reaction was then stirred for 3 hours at ambient temperature. The reaction was then chilled in an ice water bath and glacial acetic acid (14 ml) was added dropwise over 10 minutes. After stirring for 20 minutes at ambient temperature, the solvent was removed in vacuo, and the residue was extracted into water/methylene chloride (300 ml of each). The aqueous phase was extracted three times with 200 ml portions of fresh methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (49.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:30])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:29])[CH:10]=1.C([Sn](=O)CCCC)CCC.[Si]([N:45]=[N+:46]=[N-:47])(C)(C)C>C1(C)C=CC=CC=1>[N:28]1[NH:45][N:46]=[N:47][C:27]=1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[O:12][C:11](=[O:29])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:30])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCc1nn[nH]n1
Temperature: 110 °C

Procedure:
A mixture of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanenitrile (170 mg, 0.38 mmol, Example 57), dibutyltin oxide (100 mg, 0.4 mmol), TMSN3 (0.5 mL, 3.8 mmol), and anhydrous toluene (5 mL) was heated at 110° C. under N2 for 15.5 h, allowed to cool to rt, and then quenched with methanol (1 mL). The reaction was concentrated and purified by silica gel chromatography (1:0→4:1; dichloromethane:methanol) to give 8-(5-(2H-tetrazol-5-yl)pentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.51 (br s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.90 (s, 3H), 2.89 (t, 2H), 1.80-1.65 (m, 4H), 1.51 (m, 2H); MS (ESI): 490.9.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:19])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)#[CH:2].[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:19])[C:3]=2[C:1]#[CH:2])=[CH:11][CH:12]=1
Reactant: C#Cc1c(Oc2ccc([N+](=O)[O-])cc2)ccnc1N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1c(Oc2ccc(N)cc2)ccnc1N

Procedure:
3-(1-Ethynyl)-4-(4-nitrophenoxy)-2-pyridinamine (400 mg), iron powder (800 mg), ammonium chloride (1.6 g), dimethylformamide (3 ml), ethanol (1 ml) and water (1 ml) were stirred at 100° C. for 30 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added to the filtrate for extraction. The organic layer was washed 5 times with aqueous ammonium chloride solution and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 260 mg of the target substance as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>CN1C(=O)CCC1.O>[C:14]([NH:18][C:2]1[N:7]=[C:6]2[C:8]([Cl:12])=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:13])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1nc2ccnc(Cl)c2nc1Cl
Reactant: CC(C)(C)N
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nc2ccnc(Cl)c2nc1NC(C)(C)C
Temperature: 60 °C
Yield: 11.8 %

Procedure:
A glass microwave reaction vessel was charged with 3,5-dichloro-2-methylpyrido[3,4-b]pyrazine (110 mg, 0.51 mmol) and tert-butylamine (0.16 mL, 1.54 mmol) (Sigma Aldich) in NMP (1.0 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 60° C. for 2 h. The mixture was diluted with water and extracted with DCM (30 mL×3). The combined organic layers was washed with water (30 mL×3) and dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (10-30% EtOAc in Hexanes) to give N-(tert-butyl)-5-chloro-2-methylpyrido[3,4-b]pyrazin-3-amine (15 mg, 0.060 mmol, 11% yield). MS (ESI, pos. ion) m/z: 251.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N+:4]=1[O-])#[N:2].P(Br)(Br)([Br:41])=O.C(=O)([O-])O.[Na+]>C(#N)C>[Br:41][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]([NH:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([C:23]([F:35])([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=3[CH2:36][CH3:37])=[O:14])[CH:9]=2)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=1
Reactant: O=P(Br)(Br)Br
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2c(ccc(C#N)[n+]2[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc2nc(C#N)cc(Br)c2c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 43 %

Procedure:
2-Cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]-quinoline-6-carboxamide-1-oxide (96 mg) was dissolved in acetonitrile, added with phosphoryl bromide (250 mg), and stirred at 100° C. for 5 hours. After cooling to room temperature, the reaction solution was poured into ice water and neutralized with sodium hydrogen carbonate. After extracting the mixture twice with ethyl acetate, the organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was removed by distillation under the reduced pressure. The resulting residues were purified by column chromatography to obtain 4-bromo-2-cyano-N-[2-ethyl-6-methyl-4-(1,1,1,2,3,3,4,4,4-nonafluorobutan-2-yl)phenyl]quinoline-6-carboxamide (46 mg, 43%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][C:9](=O)[CH2:8][CH2:7]1.[C:12](O)(=O)C>>[CH3:12][C:9](=[O:11])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CC(=O)O
Reactant: CCCCCC1CCC(=O)O1
Product: CCCCC=CCCC(C)=O
Yield: 52 %

Procedure:
Using the same procedure as described under A) but starting with a solution consisting of γ-nonalactone (obtained according to the literature) (5.0 g, 32.0 mmoles) into 45 g of acetic acid and a supported catalyst obtained according to procedure a), there were obtained (after bulb to bulb distillation at 40 mbar, oven=190°) 3.6 g of the corresponding 5-decen-2-one (purity: 70%; yield: 52%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCNCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 81.9 %

Procedure:
0.99 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at room temperature overnight in 1.2 g (16 mmol) of diethylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/methanol 9/1 there was obtained 0.9 g (81%) of 3-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 153°-154°, which was converted into the hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:13][CH2:14]Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[OH:16][CH2:17][C:18]1[N:19]=[C:20]([CH2:63][CH2:64][CH3:65])[N:21]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:42]=[N:41][N:40]=3)=[CH:29][CH:28]=2)[C:22]=1[C:23]([OH:25])=[O:24].C(OCC)(=O)C>CN(C)C(=O)C.O>[OH:16][CH2:17][C:18]1[N:19]=[C:20]([CH2:63][CH2:64][CH3:65])[N:21]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]3[N:43]([C:44]([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:42]=[N:41][N:40]=3)=[CH:31][CH:32]=2)[C:22]=1[C:23]([O:25][CH2:14][O:13][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CO)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.2 %

Procedure:
0.30 g of potassium carbonate and 0.24 g of pivaloyloxymethyl chloride were added to a solution of 0.98 g of 4-hydroxymethyl-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid [prepared as described in step (a) above] in 10 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 0.91 g of the title compound as a gum.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH3:23])[CH2:12][CH2:13]1
Reactant: Cc1nc2ccccc2n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc2ccccc2n1C1CCNCC1
Yield: 82.8 %

Procedure:
The title compound was prepared from 120 mg of 1-(1-benzyl-piperidin-4-yl)-1-H-benzoimidazole (from Step A), 100 mg of 10% palladium on carbon and 100 mg of ammonium formate in 5 mL of MeOH using a procedure analogous to that described in Example 95, Step C to provide 70 mg of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][N:24](CC3C(OC)=CC(OC)=CC=3OC)[C:23](=[O:52])[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].Cl.C(O)(=O)C>>[NH2:1][C:2]1[CH:14]=[C:13]([C@H:15]([NH:18][C:19]([N:21]2[C:27](=[O:28])[C@@H:26]([CH2:29][C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[O:37][CH3:38])[CH2:25][NH:24][C:23](=[O:52])[CH2:22]2)=[O:20])[CH2:16][CH3:17])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC[C@@H](NC(=O)N1CC(=O)N(Cc2c(OC)cc(OC)cc2OC)C[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)OC(C)(C)C)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC[C@@H](NC(=O)N1CC(=O)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 28 %

Procedure:
(Step 2) To tert-butyl 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3,7-dioxo-4-(2,4,6-trimethoxybenzyl)-1,4-diazepan-1-yl]carbonyl}amino)propyl]benzoate (1.47 g), 1M hydrogen chloride/acetic acid solution (15 ml) was added and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated, then the residue was purified by silica gel column chromatography (chloroform/ethyl acetate/methanol/acetic acid=8/8/1/0.1) to obtain the title compound (0.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Br[CH2:15][C@@H:16]([CH3:26])[CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CCCCCCC.CCOC(C)=O>[Si:19]([O:18][CH2:17][C@@H:16]([CH3:26])[CH2:15][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:20])[CH3:21]
Reactant: C[C@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)N(C[C@H](C)CO[Si](C)(C)C(C)(C)C)C(=O)CO2
Yield: 73 %

Procedure:
6-Methoxy-4H-benzo[1,4]oxazin-3-one (111MF24) (2.7 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and Cs2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) to give the title compound (111MF32) (4.03 g, 80%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.8 Hz, 1H), 6.50 (dd, J=2.8 Hz, J=8.6 Hz, 1H), 4.53 (q, J=14.8 Hz, J=29.2 Hz, 2H), 3.98 (dd, J=8.8 Hz, J=14.0 Hz, 1H), 3.85 (dd, J=5.8 Hz, J=14.2 Hz, 1H), 3.77 (s, 3H), 3.57 (dd, J=9.2 Hz, J=10.0 Hz, 1H), 3.47 (dd, J=7.2 Hz, J=10.0 Hz, 1H), 2.20-2.12 (m, 1H), 0.91 (s, 12H), 0.05 (d, J=1.2 Hz, 6H); 13C NMR (CDCl3) δ 165.3, 155.6, 139.7, 129.8, 117.2, 107.4, 103.3, 68.0, 66.2, 55.9, 43.9, 34.3, 26.1, 18.5, 14.7, −5.3, −5.4.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)CC)[CH3:27]>CC(C)=O>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([O:14][CH2:27][C:26]#[N:28])=[O:13])=[CH:10][C:9]=1[S:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Solvent: CC(C)=O
Product: CCCCSc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
A mixture of 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid (0.78 g) chloroacetonitrile (0.17 g), triethylamine (0.42 g) and dry acetone (10 ml) is refluxed for 6 hours. After cooling, the separated triethylamine hydrochloride is removed by filtration, and the filtrate is evaporated in vacuo. The residue is crystallized by trituration with aqueous ethanol. After cooling the material is collected by filtration, washed with cold aqueous ethanol and dried. After recrystallization from aqueous ethanol, cyanomethyl 4-benzyl-3-n-butylthio-5-sulfamylbenzoate is obtained with a melting point of 112.5°-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:9]=1)=[O:6].[CH3:29][C:30]1[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:21]=[CH:22][C:23]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:37]([C:39]([F:42])([F:40])[F:41])=[N:38][C:30]=3[CH3:29])[CH:3]=2)=[O:6])=[CH:9][C:10]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Cl
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1N
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)ccc1CS(C)(=O)=O
Yield: 36.9 %

Procedure:
3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (19 mg, 0.079 mmol) via procedure V to afford 16 mg of N-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-2-(methylsulfonylmethyl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid. MS (Q1) 603 (M)+.
Reaction SMILES: C(O)(=O)C(C)=C.CC(C(OCCOC(C(C)=C)=O)=O)=C.[CH:21]([CH:24]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:26][C:27](=[O:29])[CH3:28])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:23][CH:21]([C@@H:24](/[CH:30]=[CH:31]/[C:32]([CH3:34])=[CH2:33])[CH2:25][CH2:26][C:27]([CH3:28])=[O:29])[CH3:22]
Reactant: CC(=O)CCC(CCC(C)C)C(C)C
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Solvent: Cc1ccccc1
Product: C=C(C)/C=C/[C@@H](CCC(C)=O)C(C)C

Procedure:
Methacrylic acid (3 mol percent), EGDMA (95 mol percent), and 5-isopropyl-8-methylnonan-2-one (2 mol percent) are combined in toluene. 2,2-Azobisisobutyronitrile (AIBN) is added as an initiator. The reaction flask is degassed, purged with dry nitrogen, and sealed. The solution is irradiated with a UV lamp (365 nm) to activate the AIBN and initiate the polymerization reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=O)=N2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH2:21][CH2:22][OH:23])[CH:14]=3)=[CH:11][C:10]([C:24]([N:51]3[CH2:55][C:54](=[O:56])[NH:53][CH2:52]3)=[O:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2cccc(OCCCO)c2)n(-c2cccc(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Product: O=C1CN(C(=O)c2cc(-c3cccc(OCCCO)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 116A in analogy to the synthesis of the compound of Example 23. 54 mg (69% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:23][N:24]([CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:18]([CH:16]1[CH2:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:17]1)=[O:19]
Reactant: CNCC1CCOCC1
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CC1CCOCC1)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(tetrahydro-pyran-4-ylmethyl)-amine hydrochloride (200 mg, 1.21 mmol), triethylamine (0.108 ml, 0.78 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at rt for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (87 mg, 32% yield). Rf=0.80 (20% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C23H33ClN2O, 420.9, found, 421.3 (M+1) APCI; 400 MHz 1H NMR (CDCl3) mixture of rotomers, diagnostic peaks, δ 3.98-3.88 (m, 2H), 3.73 (s, 2H), 2.95 (s, 3H), 2.62-2.54 (m, 6H), 1.70-1.46 (m, 2H), 1.38-1.17 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.[CH:15]([Mg]Br)=[CH2:16].[NH4+].[Cl-]>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]2[C:7]=1[NH:12][CH:16]=[CH:15]2
Reactant: O=[N+]([O-])c1cc(OCCCl)ccc1Cl
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: ClCCOc1ccc(Cl)c2[nH]ccc12
Reaction time: 2.25 h
Yield: 158.3 %

Procedure:
To a solution of 1-(2-chloroethoxy)-4-chloro-3-nitrobenzene (10.00 g, 0.04236 mol) in THF (230 mL) stirred in a cold bath at -50 to -40° C. was added a THF solution of vinylmagnesium bromide (132 mL, 1.0 M, 0.132 mol) over 2 minutes. After stirring in the cold bath for 2-2.5 hours, saturated NH4Cl (150 mL) was added to the cold solution and it was removed from the cold bath. Enough 1 M HCl was added to dissolve the precipitated solids. This two phase system was stirred for 0.5 hour at most. The layers were separated and the aqueous phase was extracted once with Et2O. Combination of the Et2O and THF followed by drying over MgSO4 and evaporation gave 15.43 g of a dark oil. This was purified by chromatography on silica gel using a three component elutant which consisted of 80% CH2Cl2 and 20% of a gradient of EtOAc/hexane. This gave the product as a yellow solid: 3.32 g (34%); mp 68-72° C. MS EI m/e 229, 231, 233 (M+); 1H NMR (400 MHz, DMSO-d6) δ 3.99 (t, 2H, J=5.1 Hz), 4.34 (t, 2H, J=5.0 Hz), 6.51 (t, 1H, J=2.7 Hz), 6.53 (d, 1H, J=7.8 Hz), 7.04 (d, 1H, J=8.0 Hz), 7.29 (t, 1H, J=2.7 Hz), 11.43 (s, 1H).
Reaction SMILES: ClC1C=CC(C2C3C(C)=NN(C4CN(C(OC(C)(C)C)=O)C4)C=3C(=O)N2C2C=C(C)C3N(C(C)=NN=3)C=2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:54]3[C:53]([CH2:55][O:56][CH3:57])=[N:52][N:51]([CH:58]4[CH2:60][CH2:59]4)[C:50]=3[C:49](=[O:61])[N:48]2[C:62]2[CH:67]=[C:66]([CH3:68])[C:65](=[O:69])[N:64]([CH3:70])[CH:63]=2)=[CH:43][CH:42]=1>CCCCCCC.CC(O)C>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]2[C:54]3[C:53]([CH2:55][O:56][CH3:57])=[N:52][N:51]([CH:58]4[CH2:60][CH2:59]4)[C:50]=3[C:49](=[O:61])[N:48]2[C:62]2[CH:67]=[C:66]([CH3:68])[C:65](=[O:69])[N:64]([CH3:70])[CH:63]=2)=[CH:43][CH:42]=1
Reactant: COCc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Agent: Cc1nn(C2CN(C(=O)OC(C)(C)C)C2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Solvent: CC(C)O
Solvent: CCCCCCC
Product: COCc1nn(C2CC2)c2c1[C@@H](c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O

Procedure:
The title compound (32 mg, 42% yield) was obtained enantiomerically pure (>99% ee) after chiral preparative chromatography (system: Gilson PLC 2020; column: Chiralcel OD-H 5 μm, 20×250 mm; mobile phase: heptane/iPrOH 80:20; flow: 10 mL/min; detection UV: 210 nm) of the racemic mixture of 4-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-(methoxymethyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 132).