Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28]CC)=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:31][C:32]1[CH:42]=[CH:41][C:35]([CH:36]=[N:37][CH:38]2[CH2:40][CH2:39]2)=[CH:34][CH:33]=1>C1COCC1>[O:28]=[C:26]1[C:23]2([CH2:22][CH2:21][N:20]([C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[CH2:25][CH2:24]2)[CH:36]([C:35]2[CH:41]=[CH:42][C:32]([Cl:31])=[CH:33][CH:34]=2)[N:37]1[CH:38]1[CH2:39][CH2:40]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(C=NC2CC2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(C1CC1)C2c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Cool to 0 to −10 C, a solution of diisopropylamine (6.0 mL) in THF (10 mL) and add n-butyllithium (2.5 M, 16.6 mL) dropwise. After 1 h, the reaction mixture was cooled to −78 C. Add a solution of ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (1) (10 g) in anhydrous THF (20 mL) dropwise, and stir the resulting solution at −78 C for 1.5 h. Add 4-chlorobenzylidene cyclopropylamine (8) (6.69 g) in THF (40 mL) and stir for 1 h. Warm the reaction mixture to room temperature and stir overnight. Quench the reaction mixture with saturated ammonium chloride solution and extract with EtOAc. Partition the EtOAc solution with IN HCl, then salt solution. Concentrate the dried (MgSO4) EtOAc solution in vacuo to give an amber oil (13.83 g). Absorb the amber oil (12.8 g) on Purasil 60A 230-400 mesh (˜30 mL), place in a syringe cartridge, and elute onto a Redi Sep Normal Phase Disposable Column (330 g, ISCO). Elute with hexane (one column volume) then hexane/EtOAc gradient (0% to 55% EtOAc) at 65 mL/min. Collect the title compound and concentrate the fractions in vacuo to give the title compound (9) (3.49 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cccc(-c2cccc3c2OC(CN)C3)c1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1
Yield: 58.8 %

Procedure:
Treatment of (±)-[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.76 g, 6.38 mmol) with diisopropylethylamine (2.47 g, 19.17 mmol) followed by benzyl chloroformate (1.19 g, 7.02 mmol) generally according to the procedure described for Intermediate 12 provided 1.4 g (58%) of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil. Rf=0.68 (silica, ethyl acetate:hexanes 1:2); Anal. calcd. for C24H23NO3: C, 77.19; H, 6.20; N, 3.75. Found: C, 76.88H, 6.25; N, 3.51. Chiral HPLC separation of (±)-benzyl[7-(3-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralpak AD, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=10.439 min, Chiralpak AD, ethanol:hexane 1:1); Fraction 2 (Rt=11.833 min, Chiralpak AD ethanol:hexane 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: COc1ccc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxy-phenyl)-thiazol-2-ylamine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (58.0 mg) with purity >90%. MS (pos) m/z 395.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:25]3[CH:26]=[C:27]([CH2:31]O)[CH:28]=[CH:29][CH:30]=3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:33]1(=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[NH:34]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:25]3[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=3)[CH2:31][N:34]3[C:35](=[O:42])[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]3=[O:43])=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c(-c3cccc(CO)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nccn2c(-c3cccc(CN4C(=O)c5ccccc5C4=O)c3)nc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution/suspension of {3-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-phenyl}-methanol (312 mg, 0.737 mmol), isoindole-1,3-dione (130 mg, 0.885 mmol), and PS-PPh3 (loading 2.12 mmol/g; 696 mg, 1.47 mmol) in anhydrous THF (15 mL), cooled to 0° C., DIAD (218 μL, 224 mg, 1.11 mmol) was added dropwise, under N2 atmosphere. After 10 min, the cooling bath was removed and the reaction mixture stirred at ambient temperature for 3d. The resin was filtered off on a glass frit (porosity M) and washed with large volumes of THF and then CH2Cl2. The filtrate was concentrated, adsorbed onto Hydromatrix, and the crude material (0.6843 g) was purified by chromatography on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with MeOH:CH2Cl2 0.5%→3%], yielding the title compound as a yellow solid. Sample contains ≈0.3 eq. of reduced DIAD by 1H NMR; 1H NMR (CDCl3, 400 MHz) δ 4.94 (s, 2H), 5.07 (s, 2H), 5.16 (s, 2H), 7.07 (ddd, J=8.4, 2.8, 1.2 Hz, 1H), 7.11 (d, J=5.2 Hz, 1H), 7.28-7.33 (m, 3H), 7.33-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.43-7.47 (m, 2H), 7.50 (t, J=7.6 Hz, 1H), 7.53-7.56 (m, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.72 (dd, J=5.6, 2.8 Hz, 2H), 7.74-7.77 (m, 1H), 7.86 (dd, J=5.2, 3.2 Hz, 2H), 7.92 (s, 1H); MS (ES+): m/z 552.3 (100) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.104 g, 0.199 mmol) in 2 mL DCM and TFA (0.153 mL, 1.992 mmol) was stirred for 1 h. Additional TFA (0.153 mL, 1.992 mmol) was added. After 1 h additional, the reaction was concentrated, and the material suspended in Et2O to give a solid. The solid was collected by filtration, and was dried in vacuo overnight, to give 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate) as a yellow solid. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: C(#N)C.[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=[O:10].[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH:9]([C:5]1[N:4]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:8]=[CH:7][N:6]=1)=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=Cc1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)S(=O)(=O)n1ccnc1C=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To an acetonitrile (500 mL) solution of 1H-imidazole-2-carboaldehyde (64 g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added at room temperature. The reaction solution was stirred at 50° C. for 16 hours. After the reaction solution was cooled to room temperature, the precipitated crystal was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain the crude title compound. The washing was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the crude title compound. The obtained compound was combined with the crystal obtained previously and then washed with ether to obtain the title compound (88.32 g) having the following physical properties.
Reaction SMILES: FC1C=C(C=CC=1S(C)(=NC#N)=O)CN1C(=[O:15])C2C(=CC=CC=2)C1=O.[C:26]([O:30][C:31](=[O:46])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:44])=[N:41][C:42]#[N:43])=[CH:36][C:35]=1[F:45])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:46])[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:44])(=[N:41][C:42]#[N:43])=[O:15])=[CH:36][C:35]=1[F:45])([CH3:29])([CH3:27])[CH3:28]
Reactant: CS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1F
Reactant: CS(=NC#N)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1
Product: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=NC#N)cc1F

Procedure:
The title compound is prepared following the procedure described for preparation 15c, using (2-fluoro-4-(N-cyano-S-methylsulfinimidoyl)-benzyl)-carbamic acid tert-butyl ester (preparation 18c) as starting material. ESI mass spectrum: [M+H]+=312; r.t. HPLC: 0.68 min (5-95AB).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11](O)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.S(Cl)([Cl:23])=O.CN(C=O)C>C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:19][C:18]2[C:13]([N:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: Oc1nc2ccccc2nc1-c1nc2ccccc2s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2nc1-c1nc2ccccc2s1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(benzo[d]thiazol-2-yl)quinoxalin-2-ol (251 mg, 0.900 mmol) in toluene (4500 μl) was added thionyl chloride (131 μl, 1.800 mmol) followed by DMF (69.7 μl, 0.900 mmol). The green mixture was stirred at 110° C. for 3 hr. The reaction mixture was evaporated under reduced pressure and the resulting solid was diluted with CHCl3 (30-40 ml) and the insoluble solid filtered and rinsed with CHCl3. The filtrate was evaporated under reduced pressure and the residue purified by flash chromatography on silica gel (eluted with chloroform, then dichloromethane) to provide the title compound as a light yellow solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH2:3][CH2:2]1.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]2[S:16][C:17]3[CH2:22][S@@:21](=[O:23])[CH2:20][CH2:19][C:18]=3[C:13]2=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:11]=1[Cl:32].C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[Cl:32][C:11]1[C:12]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:13]2[C:18]3[CH2:19][CH2:20][S@:21](=[O:23])[CH2:22][C:17]=3[S:16][C:14]2=[N:15][C:10]=1[CH2:9][N:8]1[C:1](=[O:7])[CH2:2][CH2:3][C:4]1=[O:6]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(-c2c(Cl)c(CN)nc3sc4c(c23)CC[S@](=O)C4)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)CCC3=O)nc3sc4c(c23)CC[S@](=O)C4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of succinic anhydride (303.25 g) in DMF (3.5.L) was added (S)-2-(aminomethyl)-3-chloro-4-(4-methoxyphenyl)-7-oxido-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (1134 g) and the mixture was stirred for 1 hour. To the mixture was slowly added carbonyldiimidazole (935.5 g), and stirred at room temperature for 22 hours and further at 36 to 38° C. for 5 hours. The reaction mixture was added dropwise to water (20 L). After stirring for 2.5 hours, crystals deposited were filtered off and washed with water (1277 g, 86.4%). This product was dissolved in a mixture of acetonitrile (8.7 L) and water (2.9 L) and treated with active carbon. Water (45 L) was added and crystals were filtered off. The crystals were suspended in acetone (2.9 L), stirred at 48 to 52° C. for 1 hour and cooled to room temperature. Crystals were filtered off to obtain the titled compound (997 g). Melting point 217–218.5° C. (decomp.) [α]D20−123.63 (c=0.00490, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([NH2:26])[C:22]([NH2:25])=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[C:3]([C:8]2[CH:16]=[CH:15][C:11]([C:12]3[NH:26][C:21]4[CH:20]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:24]=[CH:23][C:22]=4[N:25]=3)=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 65.3 %

Procedure:
To a solution of 0.64 g (2.75 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL 4N HCl was added 0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, followed by stirring at 180° C. for 6 hours. The solution was cooled to room temperature before the addition of 10% NaHCO3 (10 mL) and then extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and vacuum concentrated. The residue thus obtained was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.61 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 65%).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[F:10][C:11]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:12]=1[CH2:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)=[O:20])[CH2:15]1>>[N:1]1([CH2:6][C:7]([N:17]2[CH2:18][C@H:14]([CH2:13][C:12]3[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:11]=3[F:10])[CH2:15][C@H:16]2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)=[O:20])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1
Reactant: O=C(O)Cn1ccnn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2F)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 267, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(2,4-difluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide.
Reaction SMILES: [C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH:24]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)[CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(O)C.[Pd]>[C:1]([CH2:8][N:9]1[CH2:22][CH2:21][CH2:20][N:19]2[CH2:23][CH:24]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=3)[CH2:25][N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:36][C:37]([OH:39])=[O:38])[CH2:17][CH2:18]2)[CH2:11][CH2:10]1)([OH:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CN1CCCN2CCN(CC(=O)OC(C)(C)C)CCCN(CC1)CC(Cc1ccc([N+](=O)[O-])cc1)C2
Agent: [Pd]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(CC2CN3CCCN(CC(=O)O)CCN(CCCN(CC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 145.7 %

Procedure:
To a solution of 51 (0.42 g, 0.58 mmol) in ethanol (50 mL) was added 10% Pd/C (0.13 g). The resulting mixture was stirred under H2 (g) atmosphere at room temperature for 12 hours. The reaction mixture was filtered through a celite pad and washed with ethanol (2×20 mL). The combined filtrate was evaporated under vacuum to give an oily residue which was triturated with Et2O to provide yellow solid 28 (0.39 g, 98% yield) (2 equiv TFA calculated on the basis of mass).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4].[CH3:34][NH:35][CH3:36].C1COCC1>CO>[CH3:34][N:35]([CH3:36])[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4]
Reactant: CNC
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1cccnc1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CN(C)C)cc23)ccc1Oc1cccnc1
Yield: 99 %

Procedure:
To a solution of 2-Chloro-N-(3-{4-[3-methyl-4-(pyridin-3-yloxy)-phenylamino]-quinazolin-6-yl}-prop-2-ynyl)-acetamide (99 mg, 0.20 mmol) in MeOH (5 mL) was added a solution dimethylamine in THF (2 mL, 4.0 mmol). The resulting solution was refluxed under nitrogen for 1 hour. After concentration, the residue was further dried, dissolved in MeOH (1.0 mL), and treated with HCl gas for 3 minutes. The resulting solution was added to EtOAc with vigorous stirring to precipitate the HCl salt product as yellow solid which was collected by vacuum-filtration, rinsed with EtOAc, and further dried to give 110 mg (99%) of the title compound. 1H NMR (CD3OD) δ 2.30 (s, 3H), 2.96 (s, 6H), 4.03 (s, 2H), 4.37 (s, 2H), 7.27 (d, 1H), 7.72 (dt, 1H), 7.81(m, 1H), 7.84 (d, 1H), 8.03 (dd, 1H), 8.06 (d, 1H), 8.13 (dd, 1H), 8.59 (d, 1H), 8.68 (s, 1H), 8.81 (s, 1H), 8.84 (s, 1H); MS m/z (MH+) 467.3.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]12[CH2:23][CH2:22][C@H:21]3[C@@H:11]([CH2:12][CH2:13][CH:14]4[C@:19]3([CH3:20])[CH2:18][CH2:17][C@H:16](O)[CH2:15]4)[C@H:10]1[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[NH:25]=[N+:26]=[N-:27].B(F)(F)F.CCOCC>>[C:1]([O:4][CH2:5][C@:6]12[CH2:23][CH2:22][C@H:21]3[C@@H:11]([CH2:12][CH2:13][CH:14]4[C@:19]3([CH3:20])[CH2:18][CH2:17][C@H:16]([N:25]=[N+:26]=[N-:27])[CH2:15]4)[C@H:10]1[CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=N
Reactant: CC(=O)OC[C@@]12CCC[C@@H]1[C@@H]1CCC3C[C@@H](O)CC[C@]3(C)[C@H]1CC2
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)OC[C@@]12CCC[C@@H]1[C@@H]1CCC3C[C@@H](N=[N+]=[N-])CC[C@]3(C)[C@H]1CC2

Procedure:
Using the procedures of Example 1, acetoxy-3β hydroxy-14β androstane was treated with an aromatic solution of hydrazoic acid and boron trifluoride etherate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][S:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCSCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCSCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 257.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]([CH:16]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Product: CCCCCCC(C(=O)OCC)n1cnc2cc([N+](=O)[O-])ccc21
Yield: 22.9 %

Procedure:
5-Nitrobenzimidazole (0.109 moles, 17.8 g.) was reacted with sodium hydride (0.122 moles, 4.9 g of 60% in mineral oil) and ethyl 2-bromooctanoate (0.102 moles, 22 ml) as in Example 11 to produce a mixture of the 5 and 6 isomer. The isomers were separated to yield 7.8 g of ethyl 2-(5-nitro-1H-benzimidazol-1-yl)octanoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:11]([CH3:10])(=[O:13])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N)cc(Br)c1
Product: Cc1cc(Br)cc(NS(C)(=O)=O)c1
Yield: 99.3 %

Procedure:
3-Bromo-5-(methyl)aniline (2 g, 10.75 mmol) was treated with methanesulfonyl chloride (915 μl, 11.82 mmol) according to the method described in Preparation 15b to give 2.82 g (96% yield) of the title compound. Purity 95%.
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1>CN(C=O)C.O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[CH:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[CH2:42][CH:43]1[CH2:46][O:45][CH2:44]1)[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: BrCC1COC1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1CC1COC1
Temperature: 50 °C

Procedure:
To a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methanesulfonyl-benzonitrile (INTERMEDIATE 18, 150 mg, 0.28 mmol) in DMF (3.0 mL) is added cesium carbonate (178 mg, 0.55 mmol) and 3-bromomethyl-oxetane (83 mg, 0.55 mmol) and the mixture is stirred at 50° C. over night. The reaction mixture is diluted with DMF and water and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 35.5 mg; ESI mass spectrum [M+H]+=560; Retention time HPLC: 1.04 min (Z018_S04).
Reaction SMILES: CI.[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][C:19]2[C:29]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=S)=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:12]=1)#[N:4].Cl>C(O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:19]3[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=[CH:28][C:29]=3[N:30]=[C:31]2[NH:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)#[N:4]
Reactant: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: CI
Product: CCNc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
Methyl iodide (4.5 g) was added to a solution of ethyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-(ethylthioureido)benzoate (1.8 g) in ethanol (50 ml), and the mixture was heated under reflux for 12 hours. To the reaction mixture was added 1N-HCl (60 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water and dried. The solvent was evaporated to dryness and the residue was purified by column chromatography on silica gel to afford yellow syrup (0.96 g, 58%).