Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:27]([NH:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])=[CH:15][CH:14]=1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: O=C(Nc1ccccc1)Nc1ccc(N2CCc3ccncc3C2)cc1
Yield: 60.2 %

Procedure:
In a manner similar to that described in Example 163, 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and phenyl isocyanate (0.041 mL, 0.377 mmol) were reacted to give the title compound as an off-white solid (52 mg, 60%). 1H NMR (DMSO-d6) δ 8.53 (s, 1H), 8.42 (s, 1H), 8.39 (s, 1H), 8.31 (d, J=4.7 Hz, 1H), 7.43 (d, J=7.6 Hz, 2H), 7.33 (d, J=9.1 Hz, 2H), 7.26 (t, J=7.8 Hz, 2H), 7.18 (d, J=5.0 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.94 (t, J=7.3 Hz, 1H), 4.33 (s, 2H), 3.47 (t, J=5.9 Hz, 2H), 2.91 (t, J=5.7 Hz, 2H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.[NH2:14][C:15]([NH2:17])=[S:16]>C(O)C>[ClH:2].[ClH:1].[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([CH2:3][S:16][C:15](=[NH:14])[NH2:17])[CH:5]=1
Reactant: ClCc1cnc2ccccc2c1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1cnc2ccccc2c1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
A solution of 3-chloromethylquinoline hydrochloride (46.4 g) in ethanol (160 cc), at 70° C., is added dropwise, in the course of 10 minutes, to a suspension of thiourea (19.7 g) in boiling ethanol (110 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 10° C. The resulting crystals are filtered off, washed twice with ethanol (100 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Quinol-3-ylmethyl)-isothiourea dihydrochloride (59.3 g), melting at 226°-228° C., is thus obtained.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[CH:6][CH:5]=1.Cl.[C:25]([NH:42][C@H:43]([C:49]([OH:51])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].C(=O)(O)[O-].[Na+].Cl>CN(C=O)C>[CH:31]1[C:30]2[CH:29]([CH2:28][O:27][C:25]([NH:42][C@@H:43]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:1]([O:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([N:10]=[N+:11]=[N-:12])=[CH:8][CH:9]=3)=[O:23])[C:49]([OH:51])=[O:50])=[O:26])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
4-Azidobenzyl (4-nitrophenyl) carbonate synthesized by the method described in the literature (Bioconjugate Chem. 2008, 19, 714) (Compound tk32) (3.46 g, 11.0 mmol) was added to a suspension of Fmoc-lysine hydrochloride (Compound tk31) (4.9 g, 12.10 mmol) and sodium bicarbonate (2.77 g, 33.0 mmol) in DMF (22 mL) under ice-cooling. The reaction mixture was stirred at 25° C. for 8 hours and 1 N hydrochloric acid was then added, followed by extraction with ethyl acetate. The organic phase was washed with brine three times and dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Compound SP661) (5.5 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].C[Si](Cl)(C)C.CC1(C)[O:21][C:20](=O)[CH2:19][C:18](=[O:23])[O:17]1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:20](=[O:21])[CH2:19][C:18]([OH:23])=[O:17]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccccc1N
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccccc1NC(=O)CC(=O)O
Yield: 30 %

Procedure:
To a solution of 2-methoxybenzeneamine (1.1 g, 8.93 mmol) in DCM (90 mL) was added TMSCl (1.1 mL, 8.93 mmol) at room temperature [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. The reaction mixture was stirred for 30 mins before the addition of 2,2-dimethyl-1,3-dioxane-4,6-dione (1.29 g, 8.93 mmol) and then stirring was continued mixture for additional 2 hours. Water (1 mL) was added, and the reaction mixture was concentrated under reduced pressure. The residue was poured into saturated NaHCO3 solution, and extracted with EtOAc. The aqueous phase was collected, acidified with conc. HCl to pH˜4, extracted with EtOAc, the extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 9:1:0.1) to afford the compound 27 (0.56 g, 30% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 12.62 (bs, 1H), 9.52 (s, 1H), 8.02 (dd, 1H), 7.03 (m, 2H), 6.88 (m, 1H), 3.82 (s, 3H), 3.46 (s, 2H). MS (m/z): 210.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and m-anisidine (43 μl, 0.385 mmol) similar to Example 13 and isolated as a pale yellow solid (38 mg, 29%). 1H NMR (Acetone-d6): 9.61 (d, J=2.4 Hz, 1H), 9.42 (s, 1H), 8.76–8.70 (m, 2H), 7.57–7.53 (m, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.79–6.75 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25](OCC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].[BH4-].[Li+].O1CCCC1.Cl>CO>[OH:26][CH2:25][CH2:24][CH:21]1[S:20][C:19]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[N:23][CH2:22]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(Nc1cccc2cc(C3=NCC(CCO)S3)[nH]c12)c1cccs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
To a mixture of ethyl (2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.27 g), lithium borohydride (70 mg) and tetrahydrofuran (10 mL) was added methanol (2 mL), and the mixture was stirred at room temperature for 5 hr. Diluted hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (46 mg, yield: 19%) as colorless plate crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][NH:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH3:18])[C@H:8]([CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][N:10]([CH3:11])[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:3])([CH3:4])[CH3:2]
Reactant: CNC[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
N-Methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester (1.72 g, 6.05 mmol) was dissolved in dichloromethane (30 ml). Triethylamine (0.84 ml, 6.05 mmol) was added. The solution was cooled to −78° C. Methanesulfonyl chloride (0.47 ml, 6.05 mmol) was added dropwise. The reaction mixture was warmed to room temperature over a period of 3.5 h. It Was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (100 ml). It was washed with 10% aqueous sodium hydrogen sulfate solution (200 ml). The aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane 1:1 as eluent, to give 1.94 g of N-methyl-N-((1R)-2-(N-methyl-N-(methylsulfonyl)amino)-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:7](=[O:11])[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]Br>ClCCCl>[Br:12][CH2:9][C:8](=[O:10])[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: BrBr
Solvent: ClCCCl
Product: O=C(CBr)C(=O)c1ccccc1
Reaction time: 1.25 h
Yield: 121.9 %

Procedure:
To a solution of 1-phenyl-propane-1,2-dione (1.72 g, 0.0116 mol) in DCE (5 mL) was added Br2 (1.87 g, 0.0169 mol). The reaction mixture was stirred for 75 min. and the volatiles were removed to yield 3.21 g of 3-bromo-1-phenyl-propane-1,2-dione. The crude bromoketone (0.1046 mol) was combined at room temperature with 3-(1-cyclopentyl-thioureido)-propionic acid tert-butyl ester (7.00 g, 0.031 mol) in NMP (50 mL) following general procedure B. The reaction was purified by silica gel chromatography (gradient, hexane→8% EtOAc-hexane) to yield 3-[(4-Benzoyl-thiazol-2-yl)-cyclopentyl-amino]-propionic acid tert-butyl ester (4.0 g).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])#[N:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.N1C=CC=CC=1>C(#N)C>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:14][CH2:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To (1R,2R)-N-(cyanomethyl)-2-(hydroxymethyl)cyclohexanecarboxamide (62 mg, 0.31 mmol) in a 4 mL sample vial was added 4-toluenesulfonyl chloride (73 mg, 0.38 mmol), 0.63 mL acetonitrile and pyridine (33 SL, 0.41 mmol). The reaction mixture was stirred at ambient temperature for 5 h after which the solvent was removed on a rotary evaporator. Chromatography of the residue on silica gel with 4:96 methanol:chloroform as eluent provided ((1R,2R)-2-{[(cyanomethyl)amino]carbonyl}cyclohexyl)methyl 4-methylbenzenesulfonate as a colorless, waxy solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]C(O)=O)=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].C([N:21](CC)CC)C.ClC(OCC)=O.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:21])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCc1ccc(N(CCCl)CCCl)cc1
Agent: CCOC(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
3-[4-[N,N-Bis(2-chloroethyl)amino]phenyl]propionic acid (0.20 g; 0.69 mmol) was suspended in 1 ml of acetone and the resulting mixture was stirred under a nitrogen gas atmosphere and ice-cooling. Triethylamine (115 μl; 0.82 mmol; 1.2 equivalents) and ethyl chloroformate (79 μl; 0.82 mmol; 1.2 equivalents) were added successively. Fifteen minutes later, a solution of 90 mg (1.38 mmol; 2.0 equivalents) of sodium azide in 1 ml of water was added dropwise. The resulting mixture was stirred, as was, for 30 minutes, to which ice was added to terminate the reaction. The thus-obtained mixture was extracted three times with 15 ml portions of benzene. The benzene layers were combined, dried over sodium sulfate and then heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was added with 7.5 ml of 8N hydrochloric acid, followed by heating for 15 minutes at 100° C. The resulting mixture was concentrated under reduced pressure and the residue was diluted with water. The thus-obtained mixture was adjusted to pH 12 with concentrated aqueous ammonia, followed by extraction with ethyl acetate. The extract was dried and concentrated, whereby 0.15 g of the title compound was obtained as a brown oil. This reaction product was provided for use in the next reaction without purification.
Reaction SMILES: O[C@@H:2]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][NH:30][CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@H:2]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:4])[CH2:29]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Reactant: COc1ccc(COC(=O)[C@@H](O)CC2CC2)cc1
Product: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccc(F)c3)C2)cc1
Yield: 91.4 %

Procedure:
The title compound was prepared from 200 mg (0.8 mmol) of 2-(S)-hydroxy-3-cyclopropyl propanoic acid, 4-(methoxy)benzyl ester (from EXAMPLE 21, Step B) and 321 mg (1.0 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-(3-fluorophenyl)pyrrolidine (from EXAMPLE 20, Step H) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 396 mg (91%) of the title compound: RF: 0.59 (4:1 a/v hexanes/EtOAc); 1H NMR (300 MHz) δ 0.01-0.14 (m, 81), 0.39-0.54 (m, 2H), 0.72 (m, 11H), 0-85 (s, 9H), 1.61-1.72 (m, 2H), 2.34 (m, 1H), 2.64 (br t, 1H), 2.75 (br t, 1H), 2.95-3.17 (m, 31), 3.38-3.60 (m, 3H), 3.82 (s, 3H), 5.13 (s, 3H), 6.85-7.00 (m, 5H), 7.18-7.36 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4](OCC)=[O:5].O.[NH2:20][NH2:21]>O.CO>[NH2:1][C:2]1[N:12]=[C:11]([CH3:13])[C:10]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([CH3:18])[C:3]=1[C:4]([NH:20][NH2:21])=[O:5]
Reactant: CCOC(=O)c1c(N)nc(C)c(NC(C)=O)c1C
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(=O)Nc1c(C)nc(N)c(C(=O)NN)c1C
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2-amino-5-acetamido-4,6-dimethylnicotinate (45.3 g., 0.18 mole) and hydrazine hydrate (100 ml.) is heated in an oil bath with stirring at 120° C. for two hours. The mixture is cooled, the solid collected, and a second crop of solid obtained by evaporating the mother liquor to about half its initial volume. The combined solids melt at 293° C. (dec.), yield 38.1 g. (89%). Analytically pure compound is obtained by dissolving the solid in about six and one-half parts (volume by weight) of hot water and diluting the filtered solution with methanol. The purified product decomposed at about 309° C. with only partial melting.
Reaction SMILES: C[Si](C)(C)CCOCN1C2C=CC=CC=2N=C1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][N:17]=1>O1CCOCC1.CCOC(C)=O>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: C[Si](C)(C)CCOCn1c(-c2n[nH]c3ccccc23)nc2ccccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: c1ccc2[nH]ncc2c1

Procedure:
Preparation of 6-[5-methoxy-2-hydroxymethyl-4-(2-trimethylsilanyl-ethoxymethoxy)phenyl]-1-(2-trimethylsilanyl)-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole: 6-Iodo-1-[2-(trimethyl-silanyl)-ethoxymethyl]-3-{1-[2-(trimethyl-silanyl-ethoxymethyl]-1H-benzoimidazol-2-yl}-1H-indazole [Example 24(a), step (v)] (300 mg, 0.48 mmol) and [4-methoxy-5-(2-trimethylsilanyl)-ethoxymethoxy-2-trimethylstannanyl-phenyl]-methanol (282 mg, 0.63 mmol) were stirred in dioxane (8 mL) under argon at 98° C. for 16 h. The reaction was allowed to cool and was diluted with EtOAc. Organics were washed with sat NaHCO3 and brine, dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% EtOAc/hexanes) gave 224 mg (60%) of 6-[5-methoxy-2-hydroxymethyl(2-trimethylsilanyl-ethoxymethoxy)-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl)-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol as a faint yellow oil. 1H NMR (300 MHz, CDCl3) δ 8.70 (d, 1H, J=8.4 Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (m, 2H), 7.34-7.41 (m, 4H), 6.91 (s, 1H), 6.29 (s, 2H), 5.83 (s, 2H), 5.36 (s, 2H), 4.55 (s, 2H), 3.78-3.92 (m, 5H), 3.59-3.70 (m, 4H), 0.83-1.04 (m, 6H), 0.03 (s, 9H); 40.04 (s, 9H), −0.13 (s, 9 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH2:21][CH2:22][CH3:23])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:7]([NH2:20])[N:6]=1.C1C(=O)N([Br:32])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:32][C:10]1[N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:20])[N:6]=[C:5]([O:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:21][CH2:22][CH3:23])[N:13]=2
Reactant: CCCC(C)(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCC(C)(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 103.3 %

Procedure:
To 2-[(2,2-dimethylpentyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (372 mg) in dry chloroform (4.05 mL) at 0° C. was added NBS (209 mg) in a single portion. The reaction was warmed to room temperature and was stirred for 5 h. The mixture was taken up into DCM (20 mL) and washed with water (30 mL). The organics were separated and dried using a hydrophobic frit then concentrated in vacuo to afford the title compound as a green/brown viscous foam (475 mg).
Reaction SMILES: C(OC([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH3:23])[C:21]4[CH:24]=[CH:25][C:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:27][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH3:23])[C:21]4[CH:24]=[CH:25][C:26]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:29])=[CH:27][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1
Reactant: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C3(NC(=O)OC(C)(C)C)CC3)cc1)n2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C3(N)CC3)cc1)n2C

Procedure:
Prepared from 2-[4-(1-tert.butyloxycarbonylamino-cyclopropyl)-phenyl]-5-[(2-methoxycarbonyl-ethyl)-aminocarbonyl]-1-methyl-benzimidazole by treating with trifluoroacetic acid in methylene chloride at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[Li]CCCC.CN([CH:25]=[O:26])C.Cl>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:25]=[O:26])[S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
To a suspension of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yl)morpholine 18 (90.2 g, 0.350 mol, 1.0 equiv.) in THF (anhydrous, 1400 ml) at −78° C. was added slowly 2.5 M solution of n-BuLi in hexanes (169 ml, 0.522 mol, 1.2 equiv.). The resulting slurry was allowed to warm up to −60° C. and a clear brown solution was observed. The solution was then cooled to −78° C. and DMF (anhydrous, 38.67 g, 0.530 mole, 1.5 equiv.) was added slowly. The resulting solution was stirred at −78° C. for 0.5 hour, and warmed up slowly to 0° C. over a period of 1-1.5 hours. The solution was then poured slowly to a mixture of 0.25 M aq. hydrochloric acid (3.0 L) and ice water (1.4 L). The resulting slurry was stirred at 0-10° C. for 0.5 hour, filtered and rinsed with cold water (0.5 L). The cake was dried in vacuum oven at 55° C. for 24 hours to afford 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 19 as a light yellow solid (90.8 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 3.778 (t, J=4.8 Hz, 4H), 3.990 (t, J=4.8 Hz, 4H), 8.756 (s, 1H), 10.022 (s, 1H). LCMS (ESI pos) m/e 285 (M+1).
Reaction SMILES: O[N:2]=[C:3]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]1=[O:24].[H][H]>CO>[NH2:2][CH:3]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[CH:4]1[OH:24]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(=NO)C(=O)c3ccccc32)cc1
Reactant: [H][H]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(N)C(O)c3ccccc32)cc1
Yield: 106.6 %

Procedure:
To a suspension of 4-(hydroxyimino)-1-tosyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one (7.0 g) in methanol (300 mL) Raney nickel (11.0 g) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen gas for 15-16 h. The reaction mixture was filtered through celite, washed with methanol (150 mL×3) and evaporated under reduced pressure to give 4-amino-1-tosyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol (7.2 g, 95%). 1H NMR: (400 MHz, CDCl3) δ: 7.67 (2H, d, J=8.0 Hz), 7.55 (1H, d, J=7.6 Hz), 7.42 (2H, d, J=7.6 Hz 7.32 (1H, t, J=7.2 Hz), 7.22 (1H, t, J=7.6 Hz), 7.04 (1H, d, J=7.6 Hz), 5.53 (1H, b), 4.08 (2H, d, J=8.0 Hz), 3.1 (1H, m), 2.4 (3H, s), 1.7 (3H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[N:26]=[C:27]=[O:28].C(OCC)(=O)C>O1CCOCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[NH:26][C:27]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:17])[CH3:1])[CH:4]=2)[N:11]=[CH:12][N:13]=1)=[O:28]
Reactant: O=C=Nc1c(F)cccc1F
Reactant: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)c1cccc(Nc2cc(NC(=O)Nc3c(F)cccc3F)ncn2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A mixture of N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine (458.6 mg, 2 mmol), 2,6-difluorophenyl isocyanate (341.2 mg, 2.2 mmol) in dry dioxane (5 mL) is shaken for 2.5 h at 80° C. After cooling down, the reaction mixture is treated with ethyl acetate. The precipitate is filtered off and dried in vacuo to afford the title compound.