Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][P:14]([C:19]([F:36])([F:35])[CH:20]([OH:34])[CH2:21][C:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])([CH3:24])[CH3:23])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:16]([O:15][P:14]([C:19]([F:35])([F:36])[C:20](=[O:34])[CH2:21][C:22]([C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])([CH3:23])[CH3:24])(=[O:18])[O:13][CH2:11][CH3:12])[CH3:17]
Reactant: CCOP(=O)(OCC)C(F)(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(F)(F)C(=O)CC(C)(C)c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A solution of oxalyl chloride (2.2 mL, 2.0M in dichloromethane) was diluted with dichloromethane (3.0 mL) and cooled in a dry ice/acetone bath. To this solution was added a solution of DMSO (0.7 mL) in dichloromethane (2.5 mL) dropwise. After 10 minutes, a solution of the [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosphonic acid diethyl ester (1.10 g) in dichloromethane (3 mL) was added and the mixture was stirred for 15 minutes. Triethylamine (4.0 mL) was added, the cooling bath was removed, the reaction mixture was allowed to warm to room temperature and quenched with water and diluted with hexanes. The organic layer was separated, washed with water, dried, filtered, and concentrated in vacuo. The residue was purified by chromatography over silica gel (eluent: hexanes to hexanes-ethyl acetate (2:1) gradient) to give [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-oxopentyl]phosphonic acid diethyl ester as an oil (1.0 g, 91%).
Reaction SMILES: [CH2:1]([CH:7]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16]C)[C:13]([CH2:18][CH2:19][CH:20]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][C:11]=1[O:35]C)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].B(Br)(Br)Br.CO.Cl>ClCCl.O>[CH2:29]([CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][CH2:18][C:13]1[CH:12]=[C:11]([OH:35])[C:10]([CH2:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:15][C:14]=1[OH:16])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCC(CCCCCC)CCc1cc(OC)c(CCC(CCCCCC)CCCCCCCC)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCC(CCCCCC)CCc1cc(O)c(CCC(CCCCCC)CCCCCCCC)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
1,4-Bis-(3-hexyl-undecyl)-2,5-dimethoxy-benzene (7.000 g; 11.38 mmol) is dissolved in anhydrous dichloromethane (115 cm3) before cooling down the solution to −78° C. Neat boron tribromide (2.69 ml; 28.5 mmol) is added dropwise over 15 minutes. The resulting mixture is stirred at −78° C. for 1 hour before being warmed to 23° C. for 18 hours. Methanol (25 cm3) and then diluted HCl (75 cm3) is added before pouring the reaction mixture into water. The organic layer is separated and the aqueous layer extracted tow times with diethyl ether (2×250 cm3). The organic fractions are combined, dried over magnesium sulfate and the solvents removed under vacuum. The crude product is used, as it, without further purification (6.51 g, Yield: 97%). NMR (1H, 300 MHz, CDCl3): δ 6.54 (s, 2H); 4.24 (br, 2H); 2.47 (m, 4H); 1.51 (m, 4H); 1.26 (m; 50H); 0.88 (t, J=6.7 Hz, 12H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si](C(C)(C)C)(C)C)=[C:10]([F:22])[CH:9]=2)=[CH:4][CH:3]=1.C([Si:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37]C=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1)CCCC.Br[CH2:42][C:43]([F:48])([F:47])[CH:44]([F:46])[F:45]>>[CH2:35]([Si@H:28]1[CH2:29][CH2:30][C@H:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:42][C:43]([F:48])([F:47])[CH:44]([F:46])[F:45])=[C:10]([F:22])[CH:9]=3)=[CH:6][CH:7]=2)[CH2:32][CH2:33]1)[CH2:40][CH2:39][CH2:38][CH3:37]
Reactant: FC(F)C(F)(F)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(=O)CC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OCC(F)(F)C(F)F)c(F)c3)cc2)CC1

Procedure:
The general procedure of Example 17 was repeated using 4'-bromo-3-fluoro-4-(t-butyldimethylsiloxy)biphenyl, 4-pentyl-4-phenyl-4-silacyclohexanone, and 1-bromo-2,2,3,3-tetrafluoro-n-propane, thereby obtaining the intended compound.
Reaction SMILES: COCCOC.[CH2:7]([N:14]1[CH2:43][CH2:42][C:17]2[N:18]=[C:19](Cl)[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[C@H:24]([CH3:40])[CH2:23]3)[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:44][C:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][C:52]=2B2OC(C)(C)C(C)(C)O2)[N:47]([S:63]([C:66]2[CH:72]=[CH:71][C:69]([CH3:70])=[CH:68][CH:67]=2)(=[O:65])=[O:64])[CH:46]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOCC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([N:14]1[CH2:43][CH2:42][C:17]2[N:18]=[C:19]([C:52]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:53]=3[C:45]([CH3:44])=[CH:46][N:47]4[S:63]([C:66]3[CH:72]=[CH:71][C:69]([CH3:70])=[CH:68][CH:67]=3)(=[O:65])=[O:64])[N:20]=[C:21]([N:22]3[CH2:27][CH2:26][N:25]([S:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[C@H:24]([CH3:40])[CH2:23]3)[C:16]=2[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)CCN1S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(B4OC(C)(C)C(C)(C)O4)cccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(S(=O)(=O)c7ccccc7[N+](=O)[O-])[C@H](C)C6)n4)CN(Cc4ccccc4)CC5)cccc32)cc1
Temperature: 140 °C

Procedure:
1,2-Dimethoxyethane (6.75 mL) was added to a 20 mL microwave vial containing a mixture of (R)-6-benzyl-2-chloro-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (1.1 g, 2.03 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (0.92 g, 2.23 mmol). Then 2M aqueous Na2CO3 was added and the reaction mixture was degassed via three argon/vacuum cycles, then charged with Pd(Ph3P)4 (0.234 g, 0.203 mmol). The vial was sealed and heated via microwave irradiation at 140° C. for 90 minutes. The mixture was then cooled to room temperature and diluted with Et2O and water. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography [55-75% ethyl acetate (containing 2% EtOH)/heptanes] to afford (R)-6-benzyl-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methyl-4-((2-nitrophenyl)sulfonyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 792.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.N1C=CC=CC=1.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl.O1CCCC1>[C:29]1([O:28][C:26](=[O:27])[NH:18][C:16]2[S:15][C:5]3[C:6]([N:9]4[CH2:10][CH2:11][O:12][CH2:13][CH2:14]4)=[N:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:17]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reaction time: 3 h

Procedure:
To a stirred suspension of 500 mg (1.88 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine and 0.46 ml (5.63 mmol) pyridine in 15 ml dichloromethane and 5 ml tetrahydrofuran was added 0.28 ml (2.25 mmol) phenyl chloroformate and stirring continued at 50° C. for 3 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 535 mg 74%) (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester as a white solid. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2N)[CH2:8][CH2:7][CH2:6]1.O>CCOCC>[NH:1]1[C:13]2=[C:14]3[C:9](=[CH:10][CH:11]=[CH:12]2)[CH2:8][CH2:7][CH2:6][N:4]3[C:2]1=[O:3]
Reactant: Nc1cccc2c1NCCC2
Reactant: NC(N)=O
Solvent: CCOCC
Solvent: O
Product: O=c1[nH]c2cccc3c2n1CCC3
Temperature: 180 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
13 g (0.216 mol) of urea are added to 32 g (0.216 mol) of 1,2,3,4-tetrahydroquinolin-8-amine and the mixture is heated for 3 hours at 180° C. Boiling water is added, the reaction mixture is allowed to cool, ether is added and the mixture is stirred for 2 hours. The reaction mixture is then filtered, the precipitate is sucked dry, washed successively with water and ether and dried under vacuum. There are obtained 19 g of product which is recrystallized from isopropanol. The residue is purified by chromatography on a column of silica gel, the eluent being a dichloromethane/methanol (95/5) mixture. There are obtained 7 g of product which is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Cl:28])[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][OH:34].Cl.N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:33][OH:34])=[C:24]([Cl:28])[N:23]=[C:22]3[CH2:29][CH2:30][CH2:31][CH3:32])=[CH:16][CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1nc(Cl)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 93.6 %

Procedure:
Intermediate (4a) (12.1 g, 26.7 mmol) and NH2OH.HCl (2.4 g, 34.7 mmol) were combined in 80 mL water and 160 mL pyridine and stirred at room temperature overnight. Water (80 mL) was added and the mixture was stirred for 1 hour. The precipitate was filtered and dried to yield 11.7 g of intermediate (4b), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12](=[S:14])=S.C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C>[CH2:22]([S:14][C:12]1[N:5]2[C:4]([S:10][CH3:11])=[N:3][C:2]([F:1])=[CH:7][C:6]2=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: S=C=S
Reactant: CSc1nc(F)cc(NN)n1
Reactant: ClCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CSc1nc(F)cc2nnc(SCc3ccccc3)n12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
4-Fluoro-2-methylthio-6-hydrazinopyrimidine (15.0 g, 0.086 mol), 15.5 ml (19.7 g, 0.258 mol) of carbon disulfide, 48 ml (34.8 g, 0.344 mol) of triethylamine, and 400 ml of ethanol were combined with stirring and after 15 min heated to reflux with stirring for 2.5 hours. The resulting mixture was allowed to cool to ambient temperature and then 16.4 g (0.129 mol) of benzyl chloride was added with stirring and allowed to react for 3 hours. The volatiles were removed by evaporation under reduced pressure and the residue was dissolved in methylene chloride. The resulting solution was extracted with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with hexane and filtered to obtain 20.9 g of the title compound as a yellow-orange powder melting at 74°-77° C. There was also a small amount of 2-benzylthio-7-fluoro-5-methylthio-1,2,4-triazolo[1,5-c]pyrimidine present. The nmr and uv spectra were consistent with the assigned structure and the presence of the impurity.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:8](O)(=[O:11])CS.CC(N=NC(C#N)(C)C)(C#N)C.[C:25](OCC1OC1)(=[O:29])[C:26](C)=[CH2:27].CN(CCCCCCCCCCCC)C.C(C1C=C(O)C=CC=1O)(C)(C)C>C1(C)C=CC=CC=1>[CH3:8][O:11][C:4]1[C:2]2[C:1]([O:6][CH2:7][C:3]=2[CH:27]=[CH:26][C:25]=1[OH:29])=[O:5]
Reactant: C=C(C)C(=O)OC
Reactant: O=C(O)CS
Reactant: C=C(C)C(=O)OCC1CO1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)c1cc(O)ccc1O
Agent: CCCCCCCCCCCCN(C)C
Solvent: Cc1ccccc1
Product: COc1c(O)ccc2c1C(=O)OC2

Procedure:
A mixed solution of 95 g of methyl methacrylate, 5 g of thioglycolic acid, and 200 g of toluene was heated to 70° C. with stirring under nitrogen gas stream. To the mixture was added 1.5 g of AIBN to conduct a reaction for 8 hours. To the reaction mixture were added 7.5 g of glycidyl methacrylate, 1.0 g of N,N-dimethyldodecylamine, and 0.8 g of tert-butylhydroquinone, followed by stirring at 100° C. for 12 hours. After cooling, the reaction mixture was reprecipitated from 2 l of methanol to obtain 85 g of Macromonomer (MA-2) having an Mw of 4.5×103 as a colorless clear viscous substance.
Reaction SMILES: N#N.[CH3:3][OH:4].Cl[C:6]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=1>O1CCOCC1.CO>[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:4][CH3:3])[CH:11]=1)#[N:13]
Reactant: CO
Reactant: N#Cc1ccnc(Cl)c1
Agent: N#N
Solvent: C1COCCO1
Product: COc1cc(C#N)ccn1
Temperature: 10 °C

Procedure:
Under a stream of N2 and with cooling, Na metal (2.7 g) was added to MeOH (36 mL) with a considerable exotherm. After the Na is dissolved, a solution of 2-chloro-4-cyanopyridine (15 g) in dioxane:MeOH (1:1, 110 mL) was added via dropping funnel over a 10 min period. The reaction was heated to reflux for 3.5 h then cooled at ˜10° C. overnight. Solid was filtered off and the solid was washed with MeOH. The filtrate was concentrated to ˜60 mL and H2O (60 mL) was added to redissolve a precipitate. Upon further concentration, a precipitate formed which was washed with H2O. Further concentration produced additional solids. The solids were combined and dried in vacuo overnight at 35° C. to provide 4-cyano-2-methoxypyridine which was used as is.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:41]([Cl:42])=[CH:40][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.[Pd+2].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[Cl:42][C:41]1[C:24]([NH:23][C:2]2[N:3]=[CH:4][C:5]3[N:6]([CH3:22])[C:7](=[O:21])[C:8]4([CH2:19][CH2:20]4)[CH2:9][N:10]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:11]=3[N:12]=2)=[CH:25][C:26]([F:43])=[C:27]([CH:40]=1)[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH:34]([N:37]([CH3:39])[CH3:38])[CH2:35][CH2:36]1)=[O:29]
Reactant: CN(C)C1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: [Pd+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Nc3cc(F)c(C(=O)NC4CCC(N(C)C)CC4)cc3Cl)ncc21
Temperature: 100 °C
Yield: 28.2 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-5-chloro-N-(4-dimethylaminocyclohexyl)-2-fluoro-benzamide (Intermediate 175; 92 mg, 0.29 mmol), and XANTPHOS (16 mg, 0.03 mmol) were dissolved in 1,4-dioxane (7.5 mL). Caesium 10 carbonate (210 mg, 0.59 mmol) was added and the system purged with a stream of nitrogen for 15 minutes before tris(dibenzylideneacetone) palladium (II) (17 mg, 0.02 mmol) was added. The apparatus was evacuated and backfilled with nitrogen (×3) and then heated at 100° C. for 3 hours. The mixture was cooled, filtered and the filtrate absorbed on to an SCX column, and the column then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (49 mg, 28%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([OH:10])[C:7]2[CH:11]=[CH:12][S:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[C:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[CH:22]=[CH:21][C:20]([O:10][CH:8]2[CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]3[S:13][CH:12]=[CH:11][C:7]2=3)=[C:19]([Cl:24])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CCN1CCc2sccc2C(O)C1
Product: CCN1CCc2sccc2C(Oc2ccc(C(N)=O)cc2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-ethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 45) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([NH:10]C(OC(C)(C)C)=O)[CH:7]=[CH:6]1)=[N+:2]=[N-:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([NH2:10])[CH:7]=[CH:6]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NC1C=CC(CN=[N+]=[N-])C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCC1C=CC(N)C1
Yield: 79.3 %

Procedure:
N-[4-(azidomethyl)cyclopent-2-enyl](t-butoxy)-carboxamide (10 g, 42 mmol) was dissolved in TFA reagent (9.25 mL TFA, 0.25 mL anisole, 0.25 mL triisopropylsilane and 0.25 mL water)and DCM (25 mL), and stirred for 30 min at rt. The reaction mixture was concentrated and the residue filtered through SCX column, eluted with ammonia (2 M solution in methanol), and evaporated to yield the title compound (4.6 g, 80%).: ESMS: 139 (M+1)+. 1H NMR (CDCl3): δ 1.40-1.55 (m, 1H), 2.45-2.60 (m, 1H), 2.90-3.00 (m, 1H), 3.40 (d, 2H), 4.104.20 (m, 1H), 5.90 (s, 2H).
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([CH3:10])[C:4](=[O:11])[CH2:3]2.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([CH3:10])[CH:4]([OH:11])[CH2:3]2
Reactant: CC1C(=O)CC2(C)CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC1C(O)CC2(C)CCC1C2
Temperature: 25 °C
Yield: 94.1 %

Procedure:
1,4-Dimethyl-bicyclo[3.2.1]octan-3-one (260 g, 1.7 mol, obtained as above in EXAMPLE III) was added to a suspension of sodium borohydride (NaBH4, 19 g, 0.5 mol) in isopropanol ((CH3)2CHOH, 400 mL), and refluxed for 30 minutes. The reaction mixture was cooled to room temperature, and quenched with acetone ((CH3)2CO) followed by acetic acid. The organic layer was separated and concentrated to provide crude 1,4-dimethyl-bicyclo[3.2.1]octan-3-ol (250 g, 1.6 mol), which was then added to a solution of acetic anhydride ((CH3CO)2O, 192 g, 1.9 mol) and Na2CO3 (4 g, 0.036 mol) and aged at 60° C. for 6 hours. The reaction mixture was subsequently washed with water followed by a Na2CO3 solution. Fractional distillation of the organic layer provided acetic acid 1,4-dimethyl-bicyclo[3.2.1]oct-3-yl ester (159 g) having a boiling point of 88° C. at a pressure of 15 mmHg
Reaction SMILES: C1C=CN2CC3C=C(C(OCC)=O)C=CC=3NCC=12.[N+:20]([C:23]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:34]=[CH:33][C:24]=1[CH2:25][N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O)([O-])=O>>[CH:28]1[CH:29]=[CH:30][N:26]2[CH2:25][C:24]3[CH:33]=[CH:34][C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:23]=3[NH:20][CH2:31][C:27]=12
Reactant: CCOC(=O)c1ccc(Cn2cccc2C=O)c([N+](=O)[O-])c1
Agent: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2
Product: CCOC(=O)c1ccc2c(c1)NCc1cccn1C2

Procedure:
The hydrogenation conditions of ethyl 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine-7-carboxylate are used with 1-[2-nitro-4-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde to give 5.0 g of the desired product as a solid; mass spectrum (M+H)255.
Reaction SMILES: [Br:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Mg]Cl)C.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:7]2[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1cccnc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2Br)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.3 %

Procedure:
To a solution of 10 g (42 mmol) 2,3-dibromopyridine in 210 ml dry tetrahydrofuran at room temperature were added 22 ml (44 mmol) 2-propylmagnesium chloride solution (2.0 M in tetrahydrofuran). The reaction mixture was stirred for 1 h at room temperature. A solution of 7.9 g (44 mmol) 1-benzyl-4-piperidone in 40 ml tetrahydrofuran was added, and stirring was continued for 16 h. The reaction mixture was quenched with water, basified to pH 9 with aqueous 2 M sodium hydroxide solution and extracted with tert-butyl methyl ether (3×). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Flash-chromatography (aminopropyl-modified silica gel) gave the title compound (3.4 g, 23%) as an orange amorphous solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]2)=[O:29])=[C:26]([F:43])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:40]([O:41][CH3:42])=[CH:39][C:27]([C:28]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[CH2:33][CH2:32]5)=[O:29])=[C:26]([F:43])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCC(NC(=O)c2cc(OC)c(N)cc2F)CC1
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: CCN1CCC(NC(=O)c2cc(OC)c(Nc3ncc4c(n3)N(C3CCCCC3)CC3(CC3)C(=O)N4C)cc2F)CC1
Temperature: 110 °C
Yield: 48.7 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 54 mg, 0.17 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 50 mg, 0.17 mmol), and p-toluenesulphonic acid monohydrate (81 mg, 0.43 mmol) were stirred together in 4-methyl-2-pentanol (3 mL) and heated at 110° C. for 18 hours. The cooled reaction mixture was loaded onto an SCX-3 (5 g) column pre-wet with MeOH. The column was washed with MeOH (2 column volumes) and eluted with 2M NH3/MeOH. Solvent evaporation of the combined ammoniacal fractions gave a brown gum which was purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (48 mg, 49%)