Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC3C=CC=CC=3)=[CH:20][CH:19]=1)[CH2:12]2)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][N:13]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:12]2
Reactant: c1ccc(COc2ccc(N3Cc4ccc(OCc5ccccc5)cc4C3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(N2Cc3ccc(O)cc3C2)cc1
Yield: 42.6 %

Procedure:
5-Benzyloxy-2-(4-benzyloxyphenyl)isoindoline (400 mg) in TFA (12 mL) was refluxed under nitrogen atmosphere for 1 h and cooled. The solvents were removed under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (twice) then brine. Purification by chromatography on silica gel (eluant: dichloromethane—methanol 95:5) gave the title compound (95 mg) as a tan solid. 1H NMR (DMSO-d6): 9.35 (s, 1H), 8.53 (s, 1H), 7.14 (d, 1H, J=8.4 Hz), 6.75 (s br, 1H), 6.69 (m, 3H), 6.49 (d, 2H, J=8.7 Hz), 4.38 (m, 4H); MS: 228 (MH+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][C@@H:24]1[C@H:28]2[N:29]([C:34]([O:36][CH2:37][CH:38]3[C:50]4[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=4[C:44]4[C:39]3=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])[CH2:30][C@H:31]([S:32][CH3:33])[C@H:27]2[O:26][CH2:25]1>ClCCl>[CH3:33][S:32][C@H:31]1[CH2:30][N:29]([C:34]([O:36][CH2:37][CH:38]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=3[C:45]3[C:50]2=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:35])[C@@H:28]2[C:24](=[O:23])[CH2:25][O:26][C@H:27]12
Reactant: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS[C@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@@H]2C(=O)CO[C@H]12
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Dess-Martin periodinane (130 mg, 0.65 mmol) was added to a stirred solution of alcohol (55) (278 mg, 0.33 mmol) in dichloromethane (10 mL) under an atmosphere of argon. The mixture was stirred for 1 hour then diluted with dichloromethane (25 mL). The organic phase was washed with a mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulphate solution (1:1, 20 mL), then dried (Na2SO4), filtered and reduced in vacuo. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 60:40 to 65:35 gave ketone (56) (113 mg, 87%) as a white solid. TLC (Rf=0.24, Et2O:pentane 2:1); analytical HPLC two main peaks, Rt=15.71 and 15.91 min.; HPLC-MS 396.1 [M+H]+, 414.1 [M+H2O+Na]+, 813.2 [2M+H]+; [α]D18 −137.3° (c=2.33, CHCl3). δH (500 MHz, CDCl3) mixture of rotamers approx. 1:1; 2.15 (1.5H, s, SCH3), 2.19 (1.5H, s, SCH3), 3.30-3.38 (1H, m, CHSMe), 3.68-3.80 (1.5H, m, FmocNCH2), 3.93-4.05 (1.5H, m, 0.5×FmocNCH2 and OCH2C═O), 4.10-4.35 (2.5H, m, OCH2C═O, Fmoc-CH, and 0.5×Fmoc-CH2), 4.40-4.54 (2.5H, m 1.5×Fmoc-CH2 and FmocNCH), 4.74-4.84 (1H, m, OCHCHSCH3), 7.28-7.77 (8H, Fmoc aromatic CH); δC (125 MHz, CDCl3); 14.662 (SCH3); 47.133 (Fmoc-CH), 48.449/48.954 (CHSCH3), 50.539/53.419 (FmocNCH2), 61.005/61.420 (FmocNCH), 67.710/68.437 (Fmoc-CH2), 70.733 (OCH2C═O), 85.174/86.042 (OCHCHSCH3), 119.916, 119.987, 124.917, 124.964, 125.240, 125.448, 127.069, 127.712 and 127.969 (Fmoc aromatic CH), 141.255/141.317, 143.627, 143.778 and 144.264 (Fmoc quaternary), 154.942/155.049 (Fmoc C═O), 207.818/207.973 (ketone C═O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:9][C:10]([F:13])([F:12])[F:11].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:9][C:10]([F:11])([F:12])[F:13])[CH:4]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)c(SC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)c(SC(F)(F)F)c2)CC1
Reaction time: 24 h
Yield: 47 %

Procedure:
4-Chloro-3-trifluoromethylsulfanyl-phenylamine (683 mg; 3.00 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (598 mg; 3.00 mmol) and sodium triacetoxyborohydride (1.9 g; 9.00 mmol) are suspended in dichloroethane (25 mL) and the resulting mixture is stirred for 1 day. Acetic acid is then added (0.18 mL) and the reaction mixture is stirred for additional 9 days. The suspension is then diluted with dichloromethane (10 mL) and is washed with water (20 mL). The organic phase is then washed with aq. sat. sodium carbonate (10 mL), water (10 mL) and is then dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification of the crude by column chromatography on silica gel (dichloromethane) affords the desired product (580 mg; 1.41 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH3:12])[CH:6]=[CH:5]2.[CH2:13]([O:20][C:21]([N:23]1[C@H:25]([CH3:26])[C@@H:24]1[C:27]([O:29][CH3:30])=[O:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:30][O:29][C:27](=[O:28])[C@@H:24]([C@H:25]([CH3:26])[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[N:7]([CH2:11][CH3:12])[CH:6]=1)[NH:23][C:21]([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)[C@H]1[C@@H](C)N1C(=O)OCc1ccccc1
Reactant: CCn1ccc2cc(Cl)ccc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCn1cc([C@@H](C)[C@@H](NC(=O)OCc2ccccc2)C(=O)OC)c2cc(Cl)ccc21
Reaction time: 0.08 h
Yield: 28.3 %

Procedure:
To a solution of 5-chloro-1-ethylindole (6.17 g) and methyl (2R,3R)-N-benzyloxycarbonyl-3-methyl-2-aziridinecarboxylate (9.87 g) in dry methylene chloride (100 ml) which was cooled on an ice bath, was added boron trifluoride etherate (4 ml). The mixture was stirred for five minutes and washed with saturated sodium bicarbonate solution, treated with active charcoal, and dried over magnesium sulfate. After removal of the solvent, the crude residue was chromatographed on silica gel (100 g) (toluene as eluent) to give (αR,βR)-N-benzyloxycarbonyl-5-chloro-1-ethyl-β-methyltryptophan methyl ester (4.17 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([S:31]([C:34]2[CH:35]=[C:36]([NH:40][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[N:10][C:11]=34)=[O:24])[CH:37]=[CH:38][CH:39]=2)(=[O:33])=[O:32])[CH2:26][CH2:27][O:28][CH2:29][CH2:30]1
Reactant: COc1ccc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)cc1
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: COc1ccc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)cc1

Procedure:
The title compound was prepared from 5-(4-methoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [CAS 333761-72-1; commercially available] and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 562.4 [(M+H)+]; mp 203° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:17].C(Cl)Cl.CO>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([CH3:11])=[CH:5][N:4]=1)=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nc(SC)ncc1C
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(S(C)=O)ncc1C

Procedure:
Prepared from 2-methylsulphenyl-4-methylamino-5-methyl-pyrimidine by reacting with 3-chloro-peroxybenzoic acid in methylene chloride, Rf value: 0.23 (silica gel; methylene chloride/methanol/ conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: I[C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:27]B1OB(C)OB(C)O1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:27][C:2]1[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: N#Cc1cccc2c1c(I)nn2C1CCCCO1
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nn(C2CCCCO2)c2cccc(C#N)c12
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (50 mg, 0.142 mmol), K3PO4 (61.34 mg, 0.284 mmol), Pd(dppf)Cl2 (10.3 mg, 0.0142 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (18 mg, 0.142 mmol) in DMF (0.5 mL) under nitrogen in a sealed vial was heated at 120° C. in a microwave oven for 100 minutes. The reaction mixture was filtered and the filtrate diluted with H2O and extracted with EtOAc. The combined extracts extracts were dried (MgSO4), filtered, and concentrated in vacuo to afford 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as white solid (12 mg, 35.5%). MS (ESI): m/z=242 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([C:13]([OH:15])=O)=[C:8]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:27]2)=[O:24])=[CH:19][CH:18]=1.[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][NH:43][CH2:44][CH3:45]>>[CH3:39][N:40]([CH3:46])[CH2:41][CH2:42][N:43]([CH2:44][CH3:45])[C:13]([C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:28][CH2:27]3)=[O:24])=[CH:19][CH:18]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:15]
Reactant: COc1cccc2c(Nc3ccc(C(=O)NC4CCN(Cc5ccccc5)CC4)cc3)c(C(=O)O)cnc12
Reactant: CCNCCN(C)C
Product: CCN(CCN(C)C)C(=O)c1cnc2c(OC)cccc2c1Nc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1

Procedure:
N-[2-(Dimethylamino)ethyl]-N-ethyl-8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxamide was prepared by coupling 8-methoxy-4-[[4-[[[1-(phenylmethyl)-4-piperidinyl]amino]carbonyl]phenyl]amino]-3-quinolinecarboxylic acid and commercially available N,N-dimethyl-N'-ethylethylenediamine as described for Example 17, Step 5. The compound is purified by reverse phase HPLC on C18 silica gel (gradient elution from 0.1% trifluoroacetic acid in 5% MeCN/H2O to 100% MeCN). Neutralization of the trifluroacetate salt after concentrating the fractions from the HPLC run afforded the title compound as an amorphous solid that was triturated in ether: mp 120°-123 ° C.; 1H NMR (Me2SO-d6, 400 MHz), 1:1 mixture of amide rotamers, a: b) δ 9.00 (s, 1Ha), 8.94 (s, 1Hb), 8.54 (s, 1Ha), 8.51 (s, 1Hb), 7.99 (d, J=7.9 Hz, 1Hb), 7.96 (d, J=8.1 Hz, 1Ha), 7.73 (d, J=8.5 Hz, 2Hb), 7.69 (m, 2Ha, 1 H), 7.49 (t, J=8.1 Hz, 1 H), 7.30 (m, 5 H), 7.26 (d, J=8.3 Hz, 1 H), 6.89 (d, J=8.7 Hz, 2Hb), 6.85 (d, J=8.5 Hz, 2Ha), 3.96 (s, 3 H), 3.74(m, 1 H), 3.46(s, 2H),3.11 (m, 4H),2.80(d,J=10.4Hz, 2H),2.18(t,J=5.6 Hz, 2Hb), 2.02 (m, 2 H), 1.99 (s, 6Hb), 1.83 (s, 6Ha), 1.70 (m, 2 H, 2Ha), 1.56 (qd, J=10.8, 3.6Hz, 2 H), 0.91 (t, J=6.9 Hz, 3Hb), 0.61 (t, J=6.9 Hz, 3Ha).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Br:25])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Br:25])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1
Agent: [Ti+3]
Agent: [Cl-]
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1

Procedure:
In the manner given in Example 5B, 1-[(p-nitrophenyl)sulfonyl]-4-(o-bromophenyl)piperazine is reduced with titanium chloride (TiCl3) to give 1-[(p-aminophenyl)sulfonyl]-4-(o-bromophenyl)piperazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 72.3 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 166 and pyrrolidin-2-one (43 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (180 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:12][C:11]1[C:2]([NH:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH3:13])[CH:15]=2)(=[O:21])=[O:22])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: Cc1cccc(S(N)(=O)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 170 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A suspension of 2,3-dichloroquinoxaline (500 mg; 2.5 mmol; 1 eq), 3-methylbenzene sulfonamide (430.1 mg, 2.5 mmol, 1 eq.), dry K2CO3 (347.2 mg, 2.5 mmol, 1 eq.) in DMA (5 ml) is heated up at 170° C. in the microwave for 30 min under normal absorption. The solvent is evaporated to dryness. Water (20 ml) is added then AcOH until acidic pH. The residual suspension is left at 4° C. for 1 h and the precipitate formed is filtered off, washed with water until neutral, then ACN and dried under vacuum at 40° C. overnight, to afford 548.3 mg (65%) of the title compound. 1H NMR (DMSO-d6) δ 11.53 (brs, 1H), 7.99 (m, 2H), 7.87 (t, J=8.6 Hz, 2H), 7.77 (dt, J=1.5, 7.5 Hz, 1H), 7.67 (t, J=8.0 Hz, 1H), 7.56-7.43 (m, 2H), 2.42 (s, 3H). HPLC (max plot) 99%; Rt 3.70 min. LC/MS: (ES+): 334.2, (ES−): 332.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]3[N:27]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C#Cc1ccc(F)cc1
Reactant: Cc1cccc[n+]1N
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2c(C)cccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (3.47 g, 19.5 mmol) and 1-amino-2-methylpyridinium 2,4,6-trimethylbenzenesulfonate (6.0 g, 19.5 mmol) in dry acetonitrile (75 mL) was added, dropwise over 10 min a solution of 1,8-diazabicycloundec-7-ene (5.82 mL, 39 mmol) in dry acetonitrile (25 mL). The mixture was allowed to stir at room temperature for about 18 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between water (500 mL) and ethyl acetate (250 mL) and the organic phase separated. The aqueous was extracted with ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulfate, and the solvent removed under vacuum. The residue was purified by chromatography on silica gel using 10:1 hexanes:ethyl acetate as eluent to give the title compound as a white solid, 4.65 g (86%). 1H NMR (CDCl3) δ 8.15 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.41 (t, 1H, J=8.9 Hz), 7.19 (t, 2H, J=17.6 Hz), 6.87 (d, 1H, J=7.0 Hz), 3.89 (s, 3H), 2.85 (s, 3H). MS (+ve ion electrospray) 285 (100), (MH+).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[CH:10][N:11](C)[C:7]=2[CH:6]=[C:5]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:15]([C:31]([F:34])([F:33])[F:32])[CH:14]=2)[N:4]=1)#[N:2].[CH3:35][NH2:36]>CO.O>[CH3:35][NH:36][C:25]([C:23]1[N:24]=[C:19]([CH2:18][O:17][C:16]2[CH:29]=[CH:30][C:13]([C:5]3[N:4]=[C:3]([C:1]#[N:2])[C:8]4[N:9]=[CH:10][NH:11][C:7]=4[CH:6]=3)=[CH:14][C:15]=2[C:31]([F:33])([F:32])[F:34])[CH:20]=[CH:21][CH:22]=1)=[O:27]
Reactant: CN
Reactant: COC(=O)c1cccc(COc2ccc(-c3cc4c(ncn4C)c(C#N)n3)cc2C(F)(F)F)n1
Solvent: CO
Solvent: O
Product: CNC(=O)c1cccc(COc2ccc(-c3cc4[nH]cnc4c(C#N)n3)cc2C(F)(F)F)n1
Temperature: 120 °C

Procedure:
The mixture of methyl 6-((4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)methyl)picolinate (0.064 mmol, 30 mg) and methylamine in methanol (2M, 1 ml) was heated with microwaves at 120° C. for 10 minutes, then diluted with water (3 ml). The product was collected by filtration and washed with cold methanol (3 ml) to give 6-(4-((6-(methylaminocarbonyl)pyridin-2-yl)methoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (22 mg). 1H NMR (DMSO) δ: 8.80 (s, 1H), 8.77 (m, 1H, NH), 8.76 (s, 1H), 8.54 (m, 2H), 8.16 (m, 1H), 8.06 (d, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 5.58 (s, 2H), 4.04 (s, 3H). MS m/z 467 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.S1C=CC=C1[Li].[C:19](OCC)(=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1COCC1.CCCCCC>[CH2:23]([O:22][C:20](=[O:21])[C:19]([C:5]1[S:4][C:3]([O:2][CH3:1])=[CH:7][CH:6]=1)=[O:25])[CH3:24]
Reactant: COc1cccs1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Agent: [Li]c1cccs1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1ccc(OC)s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Methoxythiophene (15.4 g) is dissolved in 100 ml anhydrous THF and butyl lithium (0.135 moles) in hexane is added dropwise. The solution is stirred at room temperature 15 hr and then heated at reflux for 1 hr. After cooling, the clear solution is transferred to a dropping funnel by means of a siphon. The solution of thienyl lithium is added dropwise to a solution of diethyl oxalate (19.7 g) in 150 ml THF at -78° C. After stirring 2 hr at -78° C, the mixture is brought to -10° C and treated with saturated NH4C1 solution. The aqueous fraction is separated and extracted several times with ether. The combined ether extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography on silica gel (eluant = benzene) gives 5-methoxy-2-thiopheneglyoxylic acid ethyl ester (2; X1 = CH3O, X2 and X3 = H and R10 = C 2 H5); mp 136 -137° C after recrystallization from benzene-hexane.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[O:11][C:12]([CH3:27])=[C:13]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][C:18]=2[O:25][CH3:26])[N:14]=1>O1CCCC1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][C:13]2[N:14]=[C:10]([C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)[O:11][C:12]=2[CH3:27])=[C:18]([O:25][CH3:26])[CH:19]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (2.59 g) was added dropwise to a stirred suspension of 4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl alcohol (6.30 g) in tetrahydrofuran (100 ml) at 0° C. After stirring at room temperature for 1 hours, the reaction mixture was poured onto ice to give 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole as crystals (5.67 g, yield 85%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)[CH2:28]2)=[O:26])[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[C:20]([O:19][C:17](=[O:18])[CH2:16][C@H:15]([NH:24][C:25]([C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33](=[O:49])[CH2:34][CH2:35][CH:36]2[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]2)[CH2:28]1)=[O:26])[C:11]1[CH:12]=[N:13][CH:14]=[C:9]([OH:8])[CH:10]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Yield: 93.5 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-({(1S)-1-[5-(benzyloxy)pyridin-3-yl]-3-tert-butoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (1.69 g, 2.49 mmol) in ethyl acetate (73 mL) and methanol (12 mL) was stirred for 20 hours at room temperature under a hydrogen atmosphere in the presence of palladium on charcoal (10%, 170 mg). The suspension was filtrated through celite, which were washed thoroughly with methanol. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (methanol in ethyl acetate 0 to 15%) to yield 1.37 g of Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-hydroxypyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:15][C:16](=[O:19])[CH2:17]Br)(C)(C)C.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH3:10])[CH2:8][O:9][CH2:17][C:16]([OH:19])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CO)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(COCC(=O)O)c1ccccc1
Yield: 77.1 %

Procedure:
The subtitle compound (14.95 g) was prepared according to the procedure in example 6 part a using 2-phenyl-1-propanol (13.6 g), t-butylbromoacetate (19.5 g), tetrabutylammoniumbromide (3.2 g), toluene (70 ml), 50% aqueous sodium hydroxide (25 ml).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][NH:31][CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:29]=[C:28]3[CH2:30][N:31]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:32][CH2:33][C:27]3=[N:26][C:25]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCNC4)CC2)c(F)c1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(C(=O)N(C)C)C4)CC2)c(F)c1
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (10.5 mg, 0.097 mmol) was added to a solution of 3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (25.8 mg, 0.049 mmol) and triethylamine (20.5 μL, 0.146 mmol) in DCM (500 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (25.8 mg, 88%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.33 (d, J=6.3 Hz, 6H), 1.89-2.00 (m, 2H), 2.06-2.16 (m, 2H), 2.85-2.89 (m, 2H), 2.90 (s, 6H), 3.04-3.13 (m, 2H), 3.41-3.50 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 4.08-4.18 (m, 1H), 4.27 (s, 2H), 4.35-4.42 (m, 1H), 6.67 (ddd, J=9.0, 2.9, 1.5 Hz, 1H), 6.74 (dd, J=12.9, 3.0 Hz, 1H), 7.08 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+487.4.