Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.Cl[O:12][C:13]([CH3:16])(C)C.CC[C:19](OCC)=[S:20].C(N(CC)CC)C>ClCCl.C1COCC1>[CH3:19][S:20][CH:16]1[C:3]2[C:2](=[CH:10][CH:9]=[C:5]3[C:4]=2[S:8][CH:7]=[N:6]3)[NH:1][C:13]1=[O:12]
Reactant: Nc1ccc2ncsc2c1
Reactant: CCOC(=S)CC
Reactant: CC(C)(C)OCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CSC1C(=O)Nc2ccc3ncsc3c21
Temperature: -74 °C
Yield: 79.1 %

Procedure:
A 2-L three-neck round bottom flask was fitted with an internal thermometer, 250-mL addition funnel, magnetic stir bar and septa. The flask was charged with nitrogen, 200 mL of dry THF, and 6-aminobenzothiazole (15.2 g, 0.100 mol). The mixture was stirred and cooled in a dry ice-acetone bath to an internal temperature of −74° C. A solution of tert-butyl hypoclorite (11.0 g, 0.103 mol) in 50 mL of dichloromethane was added over a 15 min period. The resultant solution was stirred for an additional 3 h at dry ice-acetone bath temperature. To the reaction was then added by slow, dropwise addition a solution of ethyl methylthioacetate (13.8 g, 0.103 mol) in 50 mL of dichoromethane. The resultant solution was stirred for an additional 3 h at dry ice-acetone bath temperature. A solution of triethyl amine (25.3 g, 0.250 mol) and 50 ml of dichloromethane was added at dry ice-acetone bath temperature, and the solution was stirred for 0.5 h. The cooling bath was removed, and the reaction was allowed to warm to rt. The reaction was then concentrated to a thick residue. The thick oil was resuspended in 200 mL of ether and 600 mL of 0.25 M hydrochloric acid. The mixture was allowed to stir for 24 h. The resulting solid was filtered from the mixture and triturated with water and ether. The solid was then resuspended in cold MeOH, filtered and dried under vacuum for 16 h to yield 18.7 g (79%) of 8-methylsulfanyl-6, 8-dihydro-1-thia-3,6-diaza-as-indacen-7-one:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-])=O)=[CH:15][C:8]=2[CH2:7][CH2:6]1.C.O>CO.[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([CH2:4][C@H:3]([OH:21])[C:2]([F:1])([F:22])[F:23])[CH2:6][CH2:7][C:8]=2[CH:15]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C[C@H](O)C(F)(F)F)CC2
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)CCN(C[C@H](O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 92.7 %

Procedure:
(S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol (316 mg, 0.95 mmol) was dissolved in 10 mL methanol, 10% Pd/C, 50% wet (5:45:50, Palladium:carbon black:Water, 0.105 g) was added and the mixture was stirred under an atmosphere of Hydrogen (balloon) overnight. Filtration through Celite with methanol afforded (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (268 mg, 93%), which was used without further purification. (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (88 mg, 0.29 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.298 mmol), and 10-Camphorsulfonic acid (0.10 g, 0.43 mmol) in 2-Methoxyethanol (4 mL) were heated in a microwave vial at 120° C. for a total of 4 h. The light brown solution was diluted with 3 mL satd. bicarbonate solution, resulting in a suspension, which was added to 12 mL satd. bicarbonate solution which was thoroughly mixed and then filtered to afford the product in ˜80% purity by HPLC (93 mg). Trituration from ether gave an oil, so the material wash purified by RP-HPLC (10-30% acetonitrile:water) followed by formation of the free base with Macroporous carbonate resin to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide as off white solids (81 mg, 46%). m.p.=122-127° C.; LCMS (m/e) 608 (M+1); 1H-NMR (CD3OD, 400 MHz) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.1-7.3 (m, 3H), 7.04 (s, 1H), 4.70 (m, 1H), 3.94 (m, 1H), 3.89 (s, 3H), 3.4-3.7 (m, 6H), 3.25 (m, 4H), 2.95 (s, 3H), 2.32 (s, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.2-1.6 (m, 5H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23]C)OC)[N:16]([C:25]([O:27]C1C=CC=CC=1)=O)[CH2:15][CH2:14][CH2:13]2)(C(C)(C)C)(C)C.[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH2:44][CH:45]2[CH2:48][CH2:47][O:46]2)[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-:60]>C1COCC1>[Cl:60][CH2:47][CH2:48][CH:45]([OH:46])[CH2:44][O:43][C:41]1[C:38]([C:39]#[N:40])=[CH:37][N:36]=[C:35]([NH:34][C:25]([N:16]2[C:17]3[C:12](=[CH:11][C:10]([CH2:9][OH:8])=[C:19]([CH:20]=[O:23])[N:18]=3)[CH2:13][CH2:14][CH2:15]2)=[O:27])[CH:42]=1
Reactant: [Cl-]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Reactant: N#Cc1cnc(N)cc1OCC1CCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1OCC(O)CCCl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 105 mg, 0.222 mmol) and 6-amino-4-(oxetan-2-ylmethoxy)nicotinonitrile (intermediate 34A, 54.7 mg, 0.267 mmol) were dissolved in THF (2 ml) under argon. The resulting solution was cooled to −78° C. and treated slowly with LHMDS (1 M in THF, 0.489 ml, 0.498 mmol). The reaction mixture was stirred at −78° C. for 45 min and then slowly warmed up to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by preparative supercritical fluid chromatography (SFC 1, NH2 column). The 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(oxetan-2-ylmethoxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide containing fractions were concentrated and then dissolved in THF (2 ml) and water (2 ml) and treated with conc. HCl (0.39 ml). The reaction mixture was stirred 16 h at room temperature. The reaction mixture was quenched with aq. sat. NaHCO3 and extracted 3× with DCM. The org layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude material was treated with a small quantity of DCM and then the product was precipitated by addition of heptanes. The solid was collected by centrifugation and dried under vacuum to obtain the title compound as a white solid.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[C:4](=[O:6])=[O:5].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CCCCCCCCCC1C=CC([OH:42])=CC=1>CO>[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Ca+2:2].[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[C:4](=[O:42])([O-:6])[O-:5]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: O=C=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: O=C([O-])[O-]
Yield: 13 %

Procedure:
30 g of calcium hydroxide was suspended in 300 g of methanol and the obtained suspension was allowed to react while blowing carbon dioxide into the reaction system at 15° C. Next, 11 g of oleic acid and a mixture of 10 g of nonylphenol with 63 g of an alkylbenzene solvent were added thereto and the mixture was allowed to react by slowly elevating the temperature to 150° C. while removing the methanol and the water thus formed. After dehydrating under reduced pressure, overbased calcium oleate/carbonate (Ca=13%, metal ratio=20) was obtained as a pale brown viscous product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:28]5[CH2:29][NH:30][CH2:31][C:24]=5[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)c(F)c2c1=O
Reaction time: 8 h
Yield: 74.4 %

Procedure:
0.6 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1,2 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 1.3 ml of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) were suspended in 32 ml of acetonitrile and the suspension was refluxed for 10 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with ethanol. 0.58 g of the titled compound was obtained (yield 74%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([CH:42]3CCCCC3)=[N:38]OC=2C)=NC=1>>[CH:37]([NH:38][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:42])[CH3:36]
Reactant: COC(=O)c1ccc(OCc2c(C3CCOCC3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(C3CCCCC3)noc2C)nc1
Product: Cc1onc(C2CCOCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 74 %

Procedure:
As described for example 31e, 6-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.3 mol), instead of 6-(3-cyclohexyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester was converted, to the title compound (80 mg, 74%) which was obtained as a white solid after purification by chromatography (silica, 30 to 70% ethyl acetate in heptane). MS: m/e=360.3 [M+H]+.
Reaction SMILES: NC1C=CN(C2C(O)(C)C(O)C(CO)O2)C(=O)N=1.[C:19]([SiH2:23][O:24][C:25]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:26]1[O:30][CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:41])[CH3:40])=[N:33][C:32]2=[O:42])[C:28]([OH:44])([CH3:43])[CH:27]1[OH:45])([CH3:22])([CH3:21])[CH3:20].[C:58]([NH:65][C@H:66]([C:70](O)=[O:71])[CH:67]([CH3:69])[CH3:68])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:19]([SiH2:23][O:24][C:25]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:26]1[CH:27]([O:45][C:70](=[O:71])[CH:66]([NH:65][C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[CH:67]([CH3:69])[CH3:68])[C:28]([OH:44])([CH3:43])[CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:40])[CH3:41])=[N:33][C:32]2=[O:42])[O:30]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC1(O)C(O)C(CO)OC1n1ccc(N)nc1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
In another preferred embodiment of the present invention, compound (6) is reacted with Me2NCH(OMe)2 in DMF to form (7), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethylformamidine, which is the amino-protected form of (i); reacting (2) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (6) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (8) with N—Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (2); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally, reacting (10) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].Cl>>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[F:8])=[O:19])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 465 parts of 1,3-difluorobenzene and 133.3 parts of aluminum trichloride was added dropwise a mixture of 110.1 parts of 4-chloro-3-nitro-benzoyl chloride and 116 parts of aluminum trichloride at 70° C. After stirring for 2 hours at reflux temperature, the reaction mixture was poured into ice-water. There were added 127 parts of hydrochloric acid and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 130 parts (87.4%) of (4-chloro-3-nitrophenyl) (2,4-difluorophenyl)methanone; mp. 90.5° C.(interm. 1).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][C:20]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:40][NH2:41].C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:40]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([C:18]3([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21][C:20]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:19]3)=[CH:14][CH:13]=1)=[N:7]2)[NH2:41]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(Cl)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccnc(NN)c4cc3-c3ccccc3)cc2)CC2(C1)OCCO2
Temperature: 100 °C

Procedure:
To a solution of tert-butyl {2-[4-(5-chloro-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-9) (5 g, 9.2 mmol) in dioxane (100 mL) was added hydrazine (3.0 g, 92 mmol) and the reaction mixture was heated to 100° C. for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate, extracted with chloroform, dried over sodium sulfate, filtered and concentrated to give tert-butyl {2-[4-(5-hydrazino-3-phenyl-1,6-naphthyridin-2-yl)phenyl]-5,8-dioxaspiro[3.4]oct-2-yl}carbamate (1-10) as a yellow solid. MS (M+H)+: 540.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: N[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[OH:16][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1cc2c(cc1N)OCO2
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc2c(cc1O)OCO2

Procedure:
A mixture of methyl 6-amino-1,3-benzodioxole-5-carboxylate (6.3 g, 32 mmol), concentrated sulfuric acid (7 mL) and water (35 mL) was cooled in an ice-bath and then a mixture of sodium nitrite (2.3 g, 33 mmol) and water (15 mL) was added. The mixture was diluted with 50 mL of water and added to a boiling solution of cupric sulfate pentahydrate (35 g, 140 mmol) and water (75 mL). The mixture was heated 10 minutes at boiling and then cooled in an ice-bath and extracted with diethyl ether (3×). The combined extracts were washed with water (4×) and brine (1×), dried. (K2CO3) and concentrated. The residue was purified by column chromatography eluting with hexane/ethyl acetate (98:2-97:3) to give methyl 6-hydroxy-1,3-benzodioxole-5-carboxylate (2.7 g, 14 mmol), m.p. 100°-101° C.
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=2[CH:23]=1)=[O:21].O>O1CCCC1>[ClH:6].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:22]1[CH:32]=[CH:31][C:25]2[CH2:26][CH2:27][N:28]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[CH2:29][CH2:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: CN(CCCCC(=O)c1ccc2c(c1)CCNCC2)CCc1ccccc1Cl
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)N1CCc2ccc(C(=O)CCCCN(C)CCc3ccccc3Cl)cc2CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl isocyanate (74 μl) was added to a solution of 5-[[2-(2-chlorophenyl)ethyl](methyl)amino]-1-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-pentanone (365 mg) obtained in Example 205 in tetrahydrofuran (2 ml). After stirring at room temperature for 60 minutes, water (10 g) was added, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give a free base compound of the title compound as a pale yellow oil (330 mg). A solution of the free base compound in ethanol was treated with hydrogen chloride (ethyl acetate solution) to give the title compound as pale yellow amorphous powders (290 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
6-Aminonicotinic acid (Aldrich; 2 g, 14.48 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 1.82 g, 15.92 g) were suspended in DMF (20 mL), DIPEA (7.5 mL, 43.44 mmol) and HATU (6.05 g, 15.92 mmol) were added and the reaction stirred at ambient temperature for 18 hrs. The solvent was evaporated and the residues stirred with water (50 mL for 1 hr filtered, acidified with 2M aq HCl and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then the crude product eluted with 2M ammonia in MeOH and evaporated. The residue was dissolved in DCM with a little MeOH to help solubility and purified on silica eluting with a gradient of 10-20% 2M ammonia in MeOH/DCM. Fractions containing product combined and evaporated to give the title compound as a cream solid (1.75 g, 52%)
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]#[C:11][CH3:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([N:7]=[C:8]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CC#CC(=O)Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=CC(=Nc1ccccc1)Sc1ccccc1)Sc1ccccc1
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a suspension of 0.76 g (4.8 mmol) of N-phenyl-1-propynecarboxamide in toluene (15 mL) was added 1.0 g (4.8 mmol) of phosphorus pentachloride at room temperature and stirred for 4 hours. After removal of the solvent, the residue was dissolved in DMF (15 mL). To a solution of 1.2 mL (12 mmol) of thiophenol in DMF (15 mL) was added 0.31 g (7.1 mmol) of sodium hydride (60% in oil) under ice cooling and stirred for 0.5 hours. The mixture was added to the above-described DMF solution of the residue and stirred under ice cooling for 3 hours. After dilution with tert-butyl methyl ether (150 mL), the mixture was washed sequentially with water and a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 0.39 g of phenyl N-phenyl-3-(phenylthio)-2-butenimidothioate (hereinafter referred to as the present compound 44).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH3:10][NH2:11].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:10][NH:11][CH:6]1[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]1
Reactant: N#CC1CCC(=O)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC1CCC(C#N)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a solution of 4-cyanocyclohexanone (200 mg, 1.626 mmol) and CH3NH2 (2M in THF) (0.8 mL, 1.626 mmol) in THF:CH2Cl2 (1:1) (4.0 mL) at 0° C. was added NaBH(OAc)3 (689 mg, 3.252 mmol) and the resulting mixture was stirred at rt for 48 h. Subsequently, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with water, brine, dried over Na2SO4 and concentrated to afford 200 mg (89%) of 4-(methylamino)cyclohexanecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) 2.91 & 2.61 (two signals, 1H) 2.23-2.24 (m, 3H) 1.02-1.99 (m, 9H); ELSD/MS (Method 3) (m/z): [M+H]+ 139.06.