Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Br:4])(Br)[Br:2].[N:5]1([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH:8]=[CH:7][CH2:6]1>ClCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH2:13]([O:12][C:10]([N:5]1[CH2:9][CH:8]2[CH:7]([C:1]2([Br:4])[Br:2])[CH2:6]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrC(Br)Br
Reactant: O=C(OCc1ccccc1)N1CC=CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2C(C1)C2(Br)Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of bromoform (0.94 mL, 10.8 mmol) in 5 mL of dichloromethane was added over 1.5 hours to a stirred solution of benzyl 3-pyrroline-1-carboxylate (1.77 mL, 9.8 mmol) and benzyltriethylammonium chloride (0.055 g, 0.025 mmol) in 1:1 dichloromethane-50% aqueous NaOH (60 mL). The black solution was stirred for 18 hours at room temperature and then diluted with dichloromethane and H2O. The layers were separated and the organic phase washed with satd NH4Cl, brine, and dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (0-20% ethyl acetate-hexane) to afford 6,6-dibromo-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.Cl.[C:11]1([C:17]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:25]3[CH:21]([CH2:22][NH:23][CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:27]1([C:17]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:25]3[CH:21]([CH2:22][N:23]([C:7](=[O:9])[CH2:6][C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:24]3)[C:20](=[O:26])[CH2:19][CH2:18]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)Cc1cccs1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3cccs3)CC12
Reaction time: 1 h
Yield: 74 %

Procedure:
N,N'-Carbonyldiimidazole (0.81 g) is added to a solution of 2-(2-thienyl)acetic acid (0.71 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 1 hour at +5° C. and a solution of 7,7-diphenyl-4-perhydroisoindolone hydrochloride (1.6 g) and triethylamine (0.7 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred for 2 hours at +5° C. and for 16 hours at 20° C. and is then washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (10 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-thienyl)acetyl]-4-perhydroisoindolone (1.5 g) melting at 206° C. is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](OCC)=O)[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH2:21]([N:23](CC)CC)C.C(CC(N)=S)#N>CCO>[C:21]([CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])[N:12]=1)#[N:23]
Reactant: CCOC(=O)c1nc(-c2sc(NC(C)=O)nc2C)cs1
Reactant: CCN(CC)CC
Agent: N#CCC(N)=S
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Temperature: 25 °C

Procedure:
N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide (Intermediate 1)(1.0 g; 2.79 mmol; 1 eq.) is dissolved in EtOH (25 ml). Triethylamine (980 μl; 6.98 mmol; 2.50 eq.) and 2-cyanothioacetamide (Aldrich)(279.7 mg; 2.79 mmol; 1 eq.) are added. The mixture is stirred 2 h30 at rt. Solvents are evaporated and the crude product is purified by flash chromatography, with cyclohexane/EtOAc gradient as eluent. Compound (3) is isolated as a white-off powder (680.3 mg; 88%). HPLC (method A), Rt 2.30 min (purity: 92.79%). Compound (3) is further crystallized in EtOAc, affording a new batch as colorless needles (412.60 mg; 52.75%). 1H NMR (DMSO-d6, 300 MHz) δ 2.13 (s, 3H), 2.47 (s, 3H), 4.61 (s, 2H), 7.71 (s, 1H), 12.12 (br s, 1H). M− (ESI): 277; M+ (ESI): 279. HPLC (method A), Rt: 2.28 min (purity: 99.5%).
Reaction SMILES: [Br:1][C@@H:2]1[C@H:8]2[CH2:9][C@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[NH3:11].CO>C1COCC1>[Br:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([C:6]([NH2:11])=[O:10])[CH2:9][C@H:8]1[OH:7]
Reactant: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br
Reactant: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1

Procedure:
(1R,4S,5R)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (351a) (2.13 g, 10.4 mmol) was taken up in THF (20 mL) and treated with 0.880 ammonia (5.3 mL) at 20° C. for 24 h with stirring. The solvent was then removed in vacuo to give a white solid in quantitative yield; [α]D=+40.6° (c=1, MeOH).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29].N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: CC(C)=CCBr
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Agent: N
Product: CC(C)=CCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (27 mg, 76%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 4-bromo-2-methyl-2-butene (25 mg, 0.17 mmol). MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: [C@@H:1]1([O:12][C@@H:13]2[C@@H:22]([CH2:23][OH:24])[O:21][CH:16]([O:17][CH2:18][CH:19]=[CH2:20])[C@H:15]([OH:25])[C@H:14]2[OH:26])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CCl>N1C=CC=CC=1>[C:27]([C@@:15]1([OH:25])[C@@:14]([C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:26])[C@H:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][O:11][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@@H:6]([O:7][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:4]([O:5][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:2]2[O:3][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:22]([CH2:23][O:24][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:21][CH:16]1[O:17][CH2:18][CH:19]=[CH2:20])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Agent: CCl
Agent: Cl
Solvent: c1ccncc1
Product: C=CCOC1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.7 %

Procedure:
The compound (4.0 g, 10.46 mmol) synthesized in Example 2 (2a) was dissolved in pyridine (30 mL) and benzoyl chloride (12.1 mL, 104.24 mmol) was added thereto under ice-cooling, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was poured to 10% aqueous hydrochloric acid solution (20 mL) and methyl chloride (20 mL) and the organic layer was washed with 10% aqueous hydrochloric acid solution (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 5:1-5:2, V/V) to obtain the desired title compound (8.10 g, yield 70%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH:34]2[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]2)[CH2:30]1>>[CH:34]12[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]1)[CH2:30][N:29]([CH2:28][CH2:27][N:11]1[CH2:12][CH2:13][C:8]3[C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([CH3:17])=[CH:4][C:5]=4[O:15][C:14](=[O:16])[C:9]=3[CH2:10]1)[CH2:35]2
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1Cl)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 62.4 %

Procedure:
Prepared by the method described for Example 13 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.008 moles), 0.008 moles), triethylamine (2.3 ml, 0.017 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (1.8 g, 0.008 moles). Recrystallization from ethanol gave the product (2.0 g) as the hemihydrochloride, mp 255° C. (dec).
Reaction SMILES: C(N[C:5]1[C:6]([Cl:34])=[C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1C=CC(NCCO)=C[CH:15]=1)(=O)=O)(=O)C.C[O-].[Na+].C([I:40])C.CCOC(C)=O>C1COCC1>[CH2:14]([S:11][C:10]1[CH:9]=[CH:8][C:7]([NH:24][C:25](=[O:33])[C@:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])=[C:6]([Cl:34])[C:5]=1[I:40])[CH3:15]
Reactant: CC(=O)Nc1c(S(=O)(=O)c2ccc(NCCO)cc2)ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c1Cl
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1I
Temperature: 25 °C

Procedure:
To a stirred solution of (R)-N-[4-mercapto-3-iodo-2-chlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 29) (5.85 g) in anhydrous THF (40 ml) under argon was added sodium methoxide (0.44 g) followed by ethyl iodide (0.65 ml) and the mixture was heated under reflux for 1 hour and allowed to cool to ambient temperature. EtOAc (200 ml) was added, the organic phase was washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by flash column chromatography eluting with 5-30% EtOAc/isohexane to give the title compound (2.08 g) as a pale yellow solid. NMR (CDCl3) 1.36 (t, 3H), 1.75 (s, 3H), 2.92-2.99 (q, 2H), 7.15 (d, 1H), 8.34 (d, 1H), 8.89 (s, 1H); m/z: 452.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/C(O)=O.[NH:9]([C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)[NH2:10].[OH-].[Na+].C(Cl)(Cl)Cl>CC(C)=O.N>[C:2](=[N:10][NH:9][C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)([CH3:3])[CH3:1]
Reactant: NNc1cc2c(nn1)CCCCCCCCCC2
Reactant: O=C(O)/C=C/C(=O)O
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)=NNc1cc2c(nn1)CCCCCCCCCC2

Procedure:
1.5 g of 3-hydrazino-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[c]pyridazine fumarate are heated in 20 cc of acetone, to which a few drops of concentrated aqueous ammonia solution have been added, on a water bath for 1 hour. The mixture is cooled with ice, and the resulting crude title compound is divided between 5 cc of concentrated aqueous caustic soda solution and 20 cc of chloroform. The chloroform phase is concentrated, whereby a yellowish foam results, from which the title compound is obtained by recrystallization from absolute ethanol. M.P. 165°-166° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:75][CH3:76])[CH2:66][CH2:67][CH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][NH:71][CH2:70]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:69]([CH2:68][CH2:67][CH2:66][N:65]([CH2:75][CH3:76])[CH2:63][CH3:64])[CH2:70]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(CC)CCCC1CCCNC1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCCC1CCCN(C(=O)c2cc3ncnc(NC(C)c4nc5cc(Cl)ccc5[nH]4)c3cc2Cl)C1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 3-(3-diethylamino-propyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1.C(Cl)CCl>CC#N>[Cl:18][C:19]1[CH:32]=[CH:31][C:30]([NH:33][C:34]2[NH:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([NH:2][CH3:1])[N:8]=4)=[CH:11][C:12]=3[N:17]=2)=[CH:29][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1
Reactant: CNc1nccc(Oc2ccc(N)c(N)c2)n1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: CC#N
Solvent: ClCCCl
Product: CNc1nccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2-methylamino-pyrimidin-4-yloxy)-benzene-1,2-diamine (Step C, 300 mg, 1.3 mmol, 1.0 eq) in anhydrous CH3CN (20 mL) was added drop-wise a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (405 mg [residual imidazole present], 1.3 mmol, 1.0 eq) in anhydrous CH3CN (10 mL). The solution was stirred for 16 h at RT. EDC (250 mg, 1.3 mmol, 1.0 eq) was added and the reaction was heated to 80° C. and stirred for 2 h. The solvent was removed under reduced pressure and residue was dissolved in CH2Cl2/MeOH (50 mL). The organic solution was washed with H2O (25 mL), NaHCO3 (aq, 25 mL) and brine (25 mL). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered and concentrated. The crude was further purified by column chromatography (0-10% MeOH/CH2Cl2 with 1% NH4OH) followed by preparative TLC and finally reverse phase HPLC (5-100% H2O/CH3CN with 0.1% TFA) to yield [4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[5-(2-methylamino-pyrimidin-4-yloxy)-1H-benzimidazol-2-yl]-amine. MS m/z=479.2 (M+H)+; MW Calc'd for C24H27ClN8O: 478.20.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.[NH2:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13].C(O)C>O>[S:1]1[CH:5]=[CH:4][CH2:3][C:2]1=[N:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]
Reactant: O=Cc1cccs1
Reactant: CCOP(=O)(CN)OCC
Solvent: CCO
Solvent: O
Product: CCOP(=O)(CN=C1CC=CS1)OCC

Procedure:
11.2 g. (0.1 mol) Thien-2-aldehyde are added to 16.7 g. (0.1 mol) diethyl aminomethylphosphonate in 200 ml. absolute ethanol and the mixture is heated under reflux for 30 minutes. The water formed during the reaction is removed by azeotropic distillation. After complete evaporation of the solvent, 28 g. (about 100%) of a yellow oil are collected, which is pure according to LC, TLC and GC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:21]
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Reactant: CCCCCCN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.26 g, 3.33 mmol), hexylamine (0.410 g, 4.05 mmol), triethylamine (0.380 g, 3.76 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.29 g, 80.8% yield).
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[C:23]2[C:18](=[C:19]([NH:24][C:25](=[O:34])[C:26]3[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CN(C)C=O>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:26]=1[C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][C:15]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:14]2[SH:10])=[O:34]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1Cl
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a mixture of sodium sulfide nonahydrate (202 mg) in dimethylformamide (5 ml) was dropwise added 4-chloro-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (297 mg), and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added ice-water, and the mixture was adjusted to pH 3 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-mercaptoquinoline (260 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:14][C@H:10]([C:8]2[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]3[CH:21]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=2)[CH2:11][O:12][CH3:13])[N:26]=[CH:25][N:24]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (37 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-20% DCM in EtOAc) to afford 271 as a yellow solid (78 mg, 80%). LCMS (Method K): RT 3.52 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 8.68-8.64 (1H, m), 8.11 (1H, td, J=7.76, 1.94 Hz), 7.84 (1H, s), 7.79-7.73 (2H, m), 7.66 (1H, d, J=7.94 Hz), 7.56 (1H, ddd, J=7.52, 4.87, 0.98 Hz), 7.30-7.13 (4H, m), 6.03-5.95 (1H, m), 3.83 (2H, d, J=6.59 Hz), 3.19 (3H, s)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][C:26]([F:29])([F:28])[F:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC(F)(F)F)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {6-methoxy-2′-[(2,2,2-trifluoro-ethylamino)-methyl]-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: Cl[Si:2]([CH3:9])([CH3:8])[CH2:3][CH:4]([CH3:7])[CH2:5]Cl.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>>[CH3:8][Si:2]1([CH3:9])[CH2:3][CH:4]([CH3:7])[CH2:5][N:13]1[CH2:10][CH:11]=[CH2:12]
Reactant: CC(CCl)C[Si](C)(C)Cl
Reactant: C=CCN
Product: C=CCN1CC(C)C[Si]1(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The 1,1,4-trimethyl-2-allyl-2-aza-silacyclopentane was prepared as follows. Chlorodimethyl(3-chloro-2-methylpropyl)silane (100 g, 0.54 mol) was slowly added to 211.73 g (3.71 mol, 6.87 eq) of undistilled allyl amine resulting in an exothermic reaction. This reaction mixture was stirred at room temperature for 15 hours, heated to reflux at atmospheric pressure for 72 hours, and heated to 120° C. under about 50 psig pressure for 16 hours. The following GC-MS ratios shown in Table II exemplified the reactions progression and the spectra observed were as shown.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([N:42]5[C@H:47]([CH3:48])[CH2:46][CH2:45][CH2:44][C@@H:43]5[CH3:49])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:60]([CH3:59])(=[O:62])=[O:61])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 130a (175 mg, 0.26 mmol) in DCM (2.5 mL) was added DIPEA (184 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.72 min, m/z 741 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>O1CCOCC1.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:14][C:9]1[C:7]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:8]=2)[N:6]=[C:11]([CH3:13])[CH:10]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(O)c2cc(I)ccc2n1
Yield: 30.7 %

Procedure:
4-Iodoaniline (25 g), ethyl acetoacetate (17.8 g) and polyphosphoric acid (112.5 g) in dioxane (500 mL) were refluxed for 20 hours. The reaction was diluted with water (2 L) and solid sodium carbonate added until the solution reached pH 10.0. The resulting precipitate was isolated by filtration, washed with water and dried under vacuum. Trituration with ether gave the sub-title compound (10 g) as a white solid.