Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1.[C:15]([PH:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CO>[C:15]([P:19]([CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:5][CH:4]=1)[C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: ClCc1cccc(-c2ccccn2)n1
Reactant: CC(C)(C)PC(C)(C)C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)P(Cc1cccc(-c2ccccn2)n1)C(C)(C)C
Temperature: 50 °C
Yield: 84.9 %

Procedure:
To an oven dried 50 mL pressure vessel equipped with magnetic stirring bar was added 6-chloromethyl-2,2′-bipyridine (BPy-CH2Cl) (2.05 g, 10.00 mmol), di-tert-butyl phosphine (1.75 g, 12.00 mmol), and 30 mL MeOH in a nitrogen glove box. The flask was sealed and heated at 50° C. for 48 hrs with stirring outside the glove box. After cooling, it was reintroduced to the glove box, triethylamine (1.82 g, 18.00 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr. The solvents were removed under reduced pressure to obtain a white solid. The residue was washed with ether (3×20 mL) and the ether filtered and was removed under reduced pressure to yield a white solid. It was recrystallized from MeOH at ca. −30° C. to yield 2.67 g (85%) of 6-di-tert-butylphosphinomethyl-2,2′-bipyridine (BPy-tPNN).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29]Cl)=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:14][CH:13]=3)[C:6]=2[CH:28]=1.[C:31]([OH:35])(=[O:34])[CH2:32][CH3:33].C([O-])(O)=O.[Na+].O>CN(C)C=O>[C:31]([O:35][CH2:29][C:3]1[C:2]([Cl:1])=[CH:28][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])=[CH:14][CH:13]=3)[C:8]([CH2:10][CH3:11])=[N:9][C:5]=2[CH:4]=1)(=[O:34])[CH2:32][CH3:33]
Reactant: CCC(=O)O
Reactant: CCc1nc2cc(CCl)c(Cl)cc2n1-c1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(=O)OCc1cc2nc(CC)n(-c3ccc(CCO[Si](C)(C)C(C)(C)C)cc3)c2cc1Cl
Temperature: 60 °C
Reaction time: 7 h
Yield: 54.5 %

Procedure:
To a solution of 6-chloro-5-(chloromethyl)-1-[4-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)phenyl]-2-ethyl-1H-benzimidazole (step 2, 403 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) was added propionic acid (0.06 ml, 0.86 mmol) and NaHCO3 (144 mg, 1.72 mmol) at room temperature. The mixture was stirred at 60° C. for 7 h. The mixture was added water (50 ml) and extracted with ethyl acetate(100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (8:1/4:1) to afford 235 mg (53%) of the title compound as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH:9]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O.[NH2:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1>C1(C)C=CC=CC=1.NC1SC=CN=1>[S:18]1[CH:19]=[CH:20][N:21]=[C:17]1[N:16]=[CH:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C=Nc1nccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.2 %

Procedure:
To a stirred suspension of N-methylformanilide (67.6 g; 0.50 mole), toluene (25 g) and 2-aminothiazole (2.0 g; 0.02 mole) was added phosphorus oxychloride (45.8 mL; 0.50 mole) over 15 minutes. The temperature was maintained below 45° C. during this addition. Stirring was continued for 10 minutes, after which time a hot solution of 2-aminothiazole (48.0 g; 0.48 mole) in toluene (250 g) was added at 60°-65° C. over 45 minutes. The reaction was allowed to cool to room temperature with stirring and was quenched by dropwise addition into a mixture of 30% sodium hydroxide (325 g) and ice (300 g). The organic phase was washed with a mixture of water (100 g), sodium chloride (10 g), and sodium bicarbonate (7.5 g), followed by a saturated solution of sodium chloride (125 g); the resultant organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 98.3 g of crude product. Vacuum distillation gave pure 1 (60.0 g; 55.3%) as a yellow oil: bp 177° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.72 (S, 1H), 7.4-6.9 (m, 7H), 3.50 (S, 3H); IR(neat) 3075, 2950, 1615, 1580, 1490, 1345, 1310, 1120; MS (m/e) 217 (M+, base).
Reaction SMILES: C([S:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])C1C=CC=CC=1>O.N>[SH:8][CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCCSCc1ccccc1
Agent: N
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CCCS
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Benzylthiobutanoyl)-L-proline (1.08 g.) is dissolved in a mixture of water (4 ml.) and concentrated ammonia (2.7 ml.). After one hour stirring at room temperature, the mixture is diluted with water, filtered, extracted with ethyl acetate, and the aqueous phase is concentrated in vacuo. This ammonium salt of 1-(4-mercaptobutanoyl)-L-proline is purified by ion exchange chromatography on a column of diethylaminoethyl-Sephadex (cross linked dextran) with a gradient of ammonium bicarbonate, yield 0.7 g. The ammonium salt is dissolved in water (2 ml.) and applied to a column of Dowex 50 sulfonic acid resin analytical grade in the hydrogen form, and the free acid is eluted with water. The fractions containing the desired material (sulfhydryl reagent and carboxyl reagent positive) are pooled and freeze dried to obtain 1-(4-mercaptobutanoyl)-L-proline. The dicyclohexyl ammonium salt is produced by the procedure of Example 44, m.p. 157°-158°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([CH:35]5[CH2:37][CH2:36]5)=[O:34])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1)C1CC1

Procedure:
Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.03–7.87 (br, 1H), 7.56–7.02 (m, 8H), 6.91–6.65 (br, 1H), 3.30–3.05 (m, 4H), 2.62–2.38 (m, 3H), 2.38–2.21 (m, 2H), 1.98–1.51 (m, 15H), 1.14–1.01 (m, 2H), 0.93–0.70 (m, 2H); ESMS m/e: 508.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[CH2:2][OH:3].[C:23](O)(=[O:26])[C:24]#[CH:25].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:23]([O:3][CH2:2][CH2:1][C:4]([F:21])([F:22])[C:5]([F:19])([F:20])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:12])([F:11])[F:10])(=[O:26])[C:24]#[CH:25]
Reactant: C#CC(=O)O
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Yield: 72.1 %

Procedure:
1H,1H,2H,2H-perfluoro-1-octanol (10.1 g, 27.7 mmol) and propiolic acid (1.70 mL, 27.7 mmol) were dissolved in methylene chloride (15 mL), and the resulting solution cooled to 0° C. under nitrogen. To this was added a solution of dicyclohexylcarbodiimide (5.72 g, 27.7 mmol) and para-dimethylaminopyridine (0.034 g, 0.28 mmol) in methylene chloride (15 mL) over a 1 hour period, with stirring. The mixture was then allowed to warm to room temperature and a tan solid (dicyclohexylurea) precipitated. The reaction mixture was stirred overnight and then filtered to remove the dicyclohexylurea, and the filtrate was concentrated under vacuum to afford the crude product as a red oil. The crude product was chromatographed on a 15 cm×5 ccm silica gel column using 15% ethyl acetate in hexane to afford 8.31 g of (3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) propiolate as a yellow oil (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:14][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(F)cc1-c1ccc(Cl)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(-c2ccc(Cl)cc2)c(CBr)cn1

Procedure:
A mixture of EXAMPLE 307A (1.2 g), N-bromosuccinimide (1.06 g) and AIBN (azobisisobutyronitrile) (0.178 g) in CCl4 (30 mL) was heated under reflux for 6 hours. After cooling, the solid was filtered off. The filtrate was concentrated and loaded onto a silica gel column eluting with 3% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=O.[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1>>[CH3:13][N:14]([CH3:30])[CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([NH:29][C:7](=[O:9])[CH:6]=[CH:5][C:4]4[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=4)[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:16]1
Reactant: O=C(O)/C=C/c1cccc(F)c1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4cccc(F)c4)cc3s2)C1
Yield: 16.9 %

Procedure:
Prepare according to Method B, using trans-3-fluorocinnamic acid (98 mg, 0.590 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound (41 mg, 16%). mass spectrum (m/e): 411.2 [M+H], 409.2 [M−H].
Reaction SMILES: C(=O)(OC)[O:2][C:3](=O)[CH2:4][C@@H:5]([NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[BH4-].[Na+]>O>[C:13]([O:12][C:10]([NH:9][CH2:8][CH2:7][CH2:6][C@H:5]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:4][CH2:3][OH:2])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)OC(=O)C[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CCO)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
The filtrate of (3S)-3-{[(benzyloxy)carbonyl]amino}-6-[(tert -butoxycarbonyl) amino]hexanoyl methyl carbonate (Example Z1) is added dropwise to a suspension of 0.49 g (13.14 mmol) of sodium borohydride in 0.6 ml of water at 0° C. The mixture slowly warms to RT and is stirred overnight. The reaction solution is concentrated, and the residue is mixed with ethyl acetate and water. The organic phase is dried over magnesium sulfate, concentrated and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[CH2:30][C:31]([OH:33])=[O:32])=[O:19])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:36][Si](C)(C)C)=[N-]>CO>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18]([C:20]2[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=2[CH2:30][C:31]([O:33][CH3:36])=[O:32])=[O:19])/[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2CC(=O)O)n1C[C@H]1CCCO1
Solvent: CO
Product: COC(=O)Cc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Temperature: 20 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of Example 128A (400 mg, 0.856 mmol) in MeOH (3 mL) was added (diazomethyl)trimethylsilane (4.28 ml, 8.56 mmol). The mixture was stirred at 20° C. overnight then concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, gradient 20-100% solvent A in hexane; solvent A=10:1:0.5 ethyl acetate:methanol:triethylamine) to afford the title compound (250 mg, 0.519 mmol, 60.7% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.43 (s, 9H) 1.71-1.85 (m, 3H) 1.99-2.12 (m, 1H) 3.66 (s, 3H) 3.70-3.82 (m, 2H) 3.87 (s, 3H) 4.17-4.23 (m, 1H) 4.25-4.33 (m, 3H) 4.52-4.59 (m, 1H) 6.99 (s, 1H) 7.31 (d, J=7.80 Hz, 1H) 7.52 (dd, J=7.97, 1.53 Hz, 1H) 8.40 (d, J=1.70 Hz, 1H); MS (DCI/NH3) m/z 482 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH:16]([CH2:21][CH:22]=[CH2:23])[C:17]([O:19][CH3:20])=[O:18].C(O)(=O)C.O=[C:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])[CH2:31][CH2:30]1>ClC(Cl)C>[CH3:20][O:19][C:17]([CH:16]([NH:15][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[CH2:31][CH2:30]1)[CH2:21][CH:22]=[CH2:23])=[O:18]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CCC(N)C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C=CCC(NC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OC
Reaction time: 3 h
Yield: 103.4 %

Procedure:
Sodium triacetoxyborohydride (11.2 g, 52.6 mmol) was added to a solution of methyl 2-aminopent-4-enoate (3.4 g, 26.3 mmol), acetic acid (2.37 g, 39.5 mmol) and benzyl 4-oxopiperidine-1-carboxylate (9.21 g, 39.5 mmol) in dichloroethane (60 mL) at room temperature. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3×), dried over sodium sulfate, filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 0 to 8% methanol in methylene chloride gradient elution), which gave the title compound (9.42 g). MS 347.2 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16]([NH2:18])=[O:17])=[C:14]([OH:19])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:20].N[C:23]1[S:24][CH:25]=[CH:26][N:27]=1>>[CH3:1][N:2]1[C:15]([C:16]([NH:18][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:17])=[C:14]([OH:19])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:20]
Reactant: Nc1nccs1
Reactant: CN1C(C(N)=O)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O
Yield: 46 %

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-(2-thiazolyl)-1,2-thiazino-[5,6-b]indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 36 from 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxamide-1,1-dioxide and 2-amino-thiazole with a yield of 46% of theory; M.p.: 260°-261° C. (decomp.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[N:28]([CH3:30])[CH3:29])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:31][CH2:32][CH2:33][CH2:34][P:35](=[O:42])([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38]>CCCCO>[CH3:29][N:28]([CH3:30])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([NH:31][CH2:32][CH2:33][CH2:34][P:35](=[O:42])([O:36][CH2:37][CH3:38])[O:39][CH2:40][CH3:41])[N:11]=2)[CH2:14][CH2:15]1
Reactant: COc1cccc(N(C)C)c1CN1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Reactant: CCOP(=O)(CCCN)OCC
Solvent: CCCCO
Product: CCOP(=O)(CCCNc1nc(NC2CCN(Cc3c(OC)cccc3N(C)C)CC2)c2ccccc2n1)OCC
Temperature: 117 °C

Procedure:
Following General Procedure D, Compound 47 (50 mg, 0.12 mmol) and diethyl 3-aminopropylphosphonate (69 mg, 0.36 mmol) in n-BuOH (3 mL) were heated to 117° C. for 24 h with a reflux condenser. The product (Compound 81) was purified by preparative silica gel TLC plate 1000μ using 5% (7N NH3-MeOH) and 95% CH2Cl2 solution as eluent.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][OH:27])[C:20]=4[CH:28]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[CH:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][S:30]([CH3:29])(=[O:32])=[O:31])[C:20]=4[CH:28]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCO)c4c2)CCC3)n1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncn(CCCOS(C)(=O)=O)c4c2)CCC3)n1
Yield: 57.8 %

Procedure:
Stir a solution of 3-[6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-benzoimidazol-1-yl]-propan-1-ol (Example 56; 257 mg, 0.67 mmol) and methanesulfonyl chloride (200 μl, 2.06 mmol) in dry pyridine (5 mL) for 2 h. Remove the pyridine in vacuo and dissolve the residue in excess chloroform. Wash the organic layer with saturated sodium bicarbonate and dry over sodium sulfate. Filter and concentrate in vacuo to give the product as a white foam (175 mg, 55%). MS ES+ m/e 452.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)OC1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:29][N:28]1[C:24]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=2)=[CH:25][CH:26]=[N:27]1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: COC(=O)c1cc(Br)cs1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)cs1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-bromo-2-thiophenecarboxylate (1 g, 4.52 mmol) in dioxane/H2O (5:1, 16 mL) was added K2CO3 (2.7 g, 19 mmol), bis(tri-t-butylphosphine)palladium(0) (116 mg, 0.226 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (1.2 g, 5.88 mmol). The reaction mixture was heated to 80° C. in a sealed tube. After 1 h, the reaction was partitioned between H2O-DCM and the aqueous phase was extracted several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly: LCMS (ES) m/z 223 (M+H)+.
Reaction SMILES: [I:1][C:2]1[S:6][C:5]([NH:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:4][C:3]=1[C:20]([F:23])([F:22])[F:21].P(Cl)(Cl)(Cl)(Cl)[Cl:25].P(Cl)(Cl)(Cl)=O>>[I:1][C:2]1[S:6][C:5]([N:7]=[C:8]([Cl:25])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:4][C:3]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=C(Nc1nc(C(F)(F)F)c(I)s1)c1cccc(C(F)(F)F)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cccc(C(Cl)=Nc2nc(C(F)(F)F)c(I)s2)c1

Procedure:
N-(5-Iodo-4-trifluoromethylthiazol-2-yl)-3-trifluoromethylbenzamide (9.3 g was mixed with phosphorous pentachloride (4.2 g) and phosphorous oxychloride (25 ml) and the mixture was refluxed for 7 hr. The excess phosphorous oxychloride was removed under reduced pressure and the residue was mixed with cold water then extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure then the residue was recrystallized from chloroform-n-hexane to give N-(5-iodo-4-trifluoromethylthiazol-2-yl)-3-trifluoromethylbenzimidoyl chloride as yellow needles (8.5 g), m. p. 136-137° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]([NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[S:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl[CH2:28]C(O)=O>O>[CH2:1]([N:5]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1[S:7][CH:28]=[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[N:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=S)NC(=O)c1ccc(C(C)(C)C)cc1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)c1nc(-c2ccc(C(C)(C)C)cc2)cs1
Yield: 49.7 %

Procedure:
To a mixture of 174.15 g (0.50 mol) of N,N-di-n-butyl-N′-(4-t-butylbenzoyl)thiourea (compound 1-2), 44.0 g (1.10 mol) of sodium hydroxide and 500 ml of water was added 56.70 g (0.60 mol) of chloroacetic acid. The mixture was stirred and heated on a steam bath for 22 hrs and cooled. The water phase was decanted from the solid phase, and the solid was washed with water and methanol. Recrystallization of the solid from methanol gave 85.6 g (49.7% yield) of product; mp: 48.5-49.5° C. The NMR spectrum was consistent with the proposed structure. Anal. Calcd. for C21H32N2S: C, 73.20; H, 9.36; N, 8.13; S, 9.30. Found: C, 73.04; H, 9.29; N, 8.02; S, 9.19.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:25][C:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[CH:28][N:27]=1>O1CCOCC1.O.[Pd]>[F:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:16]=[CH:15][C:5]3[N:6]=[C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CCOC(=O)Cc1nc2ccc(Br)cc2s1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1nc2ccc(-c3ccnc(F)c3)cc2s1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
SiliaCat DPP-Pd (0.26 mmol/g loading, from Silicycle, 100 mg, 0.67 mmol), ethyl 2-(6-bromobenzo[d]thiazol-2-yl)acetate (described in WO2011/074560, 200 mg, 0.67 mmol), potassium phosphate (348 mg, 2.00 mmol) and (2-fluoropyridin-4-yl)boronic acid (141 mg, 1.00 mmol) in dioxane (5 mL)/water (0.2 mL) were purged with argon for 5 minutes and then heated at 90° C. After 4 hours, the reaction mixture was diluted with water (50 mL), extracted with DCM (3×50 mL), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes over 15 minutes) to give Compound B23a (120 mg, 57% yield) as a brown solid. HPLC: RT=0.95 min (LCMS Method M). MS (ES): m/z=316.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.7 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.12 (d, J=8.5 Hz, 1H), 8.02 (dd, J=8.5, 1.9 Hz, 1H), 7.81 (d, J=5.2 Hz, 1H), 7.64 (s, 1H), 4.38 (s, 2H), 4.19 (q, J=7.1 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[I-].[Li+]>ClC1C=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [I-]
Agent: [Li+]
Solvent: Clc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 115 °C
Yield: 94.09 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in chlorobenzene (70 mL) respectively, then heated to 115° C. and lithium iodide (0.23 g, 1.72 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.85 g, yield: 94.09%).