Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)/[C:10](/[CH3:18])=[C:11](\[O-])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1)#[N:2].[Li+].Cl.[NH2:22][NH2:23]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[NH:23][N:22]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=2[CH3:18])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NN
Reactant: CCOC(=O)/C([O-])=C(\C)C(=O)c1cccc(C#N)c1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1n[nH]c(-c2cccc(C#N)c2)c1C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of lithium (Z)-4-(3-cyanophenyl)-1-ethoxy-3-methyl-1,4-dioxobut-2-en-2-olate (400 mg, 1.51 mmol, Eq: 1.00) in Ethanol (10 ml) was added Hydrazine hydrochloride (113 mg, 1.65 mmol, Eq: 1.093) at rt to give an orange solution. The resulting mixture was stirred overnight at the same temperature. After 1 day the solvent was removed under reduce pressure and to the mixture was added brine. The solution was extracted two times with AcOEt, and the combined organic layers were dried over MgSO4, filtered and concentrated to give the desired compound as a yellow gum (114 mg, 26.6%). MS (ISP): 256.0 ([M+H]+).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Product: O=C(O)c1ccc(NCC(O)C(O)C(O)C(O)CO)cc1

Procedure:
As starting materials D-glucose and p-amino-benzoic acid were used. The reductive amination was carried out using Raney nickel as catalyst and heating for 2 hours to 50° C. and for 3 hours to 70° C. The product obtained had a melting point of 111° to 112° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21]1)[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1.Cl.[OH-:34].[NH4+]>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[C:5]([CH2:19][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25]3)=[N:4][C:3]3[C:2](=[O:34])[NH:10][CH:9]=[N:8][C:7]2=3)=[CH:17][CH:16]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3c(Cl)ncnc32)cc1
Reactant: [OH-]
Agent: Cl
Agent: [NH4+]
Product: O=c1[nH]cnc2c1nc(CC1CCN(Cc3ccccc3)CC1)n2Cc1ccc(F)cc1
Yield: 52 %

Procedure:
A mixture of 3 parts of 6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purine and 50 parts of a hydrochloric acid solution 1N was stirred and refluxed for 1.5 hours. After cooling, the mixture was made alkaline with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 1.5 parts (52%) of 9-[(4-fluorophenyl)methyl]-1,9-dihydro-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-6H-purin-6-one; mp. 197.0° C. (compound 185).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[CH3:19][C@H:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:21]1([C@@H:20]([NH:27][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]2[C:15]([O:17][CH3:18])=[O:16])[CH3:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (13.29 g, 51.6 mmol, 1 eq.), (S)-(−)-α-methylbenzylamine (6.66 mL, 51.6 mmol, 1 eq.), acetic acid (5.91 mL, 103.0 mmol, 2 eq.) and benzene (200 mL) were mixed at room temperature then refluxed using a Dean-Stark trap for 4 hours. Cooled to 0° C. Added acetic acid (23.66 mL, 412.8 mmol, 8 eq.) followed by the addition of sodium triacetoxyborohydride (21.90 g, 103.0 mmol, 2 eq.). Stirred for 20 minutes at 0° C. then allowed the reaction to warm to room temperature and stirred for 20 hours. Worked up by carefully (foaming) adding sodium carbonate until the pH=10. Extracted the aqueous 3 times with ethyl acetate. The ethyl acetate layers were combined, rinsed once with brine, then dried over sodium sulfate and stripped to give (3R,4S)-1-tert-butyl 3-methyl 4-((1S)-1-phenylethylamino)-piperidine-1,3-dicarboxylate (18.7 g) of an oil as product. Yield=100%. Mass Spec (ESI) detects (M+H)+=363.2.
Reaction SMILES: C1(C[O:8][C:9]2[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:37])[CH3:36])=[O:32])[CH2:26][CH2:25]3)=[C:13]3[C:18]=2[NH:17][C:16](=[O:19])[CH2:15][CH2:14]3)C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][CH2:34][CH:35]([CH3:36])[CH3:37])=[O:32])[CH2:26][CH2:25]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH2:15][CH2:14]2
Reactant: CC(C)COC(=O)NC1CCN(CC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)NC1CCN(CC(O)COc2ccc(O)c3c2CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-Phenylmethoxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril, the compound from Step A above (160 mg), was dissolved in ethanol (15 mL). Palladium (10% on carbon) was added, and the mixture was stirred under hydrogen at room temperature for 48 hours. The catalyst was removed by filtration, and the solvent evaporated to give 100 mg of crude product which was recrystallized from aqueous ethanol, yielding the title compound, 8-hydroxy-3,4-dihydro-5-[2-hydroxy-3-(4-(isobutoxycarbonylamino)-1-piperidyl)propoxy]carbostyril, m.p. 199°-200° C.
Reaction SMILES: [C:1]([CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:17][CH2:18][CH:19]([OH:29])[C:20]2[N:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[S:23][CH:24]=2)[CH3:16])=[CH:10][CH:9]=1)[CH3:7])([O:3][CH3:4])=[O:2].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=O>>[C:1]([CH:5]=[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]([N:17]2[CH2:18][CH:19]([C:20]3[N:21]=[C:22]([C:25]([F:27])([F:28])[F:26])[S:23][CH:24]=3)[O:29][CH:31]2[C:30]([O:34][CH3:35])=[O:33])[CH3:16])=[CH:12][CH:13]=1)[CH3:7])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Reactant: COC(=O)C=O
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CC(c3csc(C(F)(F)F)n3)OC2C(=O)OC)cc1

Procedure:
Prepared by analogy to Example 18 by reaction of N-[2-(4-(2-carbomethoxy-1-methylethenyl)phenyl)-1-methyl-ethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)- ethanamine with methyl glyoxylate followed by purification of the base on a silica gel column using chloroform/petroleum ether/ethyl acetate=5:4.5:0.5 as eluant.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:12][CH2:13]OC(=O)C)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[ClH:18]>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([O:12][CH2:13][Cl:18])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)OCOC(COC(C)=O)COC(C)=O
Solvent: ClCCl
Product: CC(=O)OCC(COC(C)=O)OCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.34 g (17.5 mmole) of acetoxymethyl 1,3-diacetoxy-2-propyl ether in 45 ml of methylene chloride was stirred at room temperature as a gentle stream of HCl was passed through it. After 2 hours the HCl stream was removed. The flask was stoppered and allowed to stir overnight at room temperature. Then the flask was placed in a water bath at 25°-30°, and the solution was purged with a stream of N2 to remove most of the excess HCl. The remaining solution was concentrated by rotary evaporation. In order to remove traces of HCl, the residual oil was taken up in toluene and concentrated under high vacuum at room temperature. This process was repeated three more times. After vacuum drying at room temperature, the yield of colorless residual oil was 3.83 g (97%). The NMR spectrum indicated complete conversion to product.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:1]([CH:9]([Br:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccccc1

Procedure:
To a stirred solution of benzoylacetic acid, ethyl ester (0.01 mol) in a solvent such as, for example, chloroform is added N-bromosuccinimide (NBS, 0.01 mol), and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of benzoyl-bromoacetic acid, ethyl ester is formed, ethyl acetate is added, and the mixture is rotary evaporated to remove chloroform. To the resulting ethyl acetate mixture is added thiocarbamic acid, benzyl ester, which may be prepared as described in Step (a) above, and a suitable non-nucleophilic base such as those described in Example 17 above, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the reaction is washed with 0.01 M hydrochloric acid, water, brine, and dried over sodium sulfate. The mixture is rotary evaporated to give 2-benzyloxy-4-phenyl-thiazol-5-carboxylic acid, ethyl ester, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.[NH:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:43]([C:47]([OH:49])=O)[CH:44]([CH3:46])[CH3:45].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:42]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:43]([C:47]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)=[O:49])[CH:44]([CH3:45])[CH3:46]
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1

Procedure:
Using 300 mg Boc-Cys(MBzl)-Phe-Gly-Gly-OH, 118 mg Boc-Val-OH, 110 mg HONB and 124 mg DCC, the desired product was obtained in the same manner as in Example 1-(XXI).
Reaction SMILES: [C:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[N:9]=[C:8]([F:14])[C:7]=1Cl)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]1[CH:7]=[C:8]([F:14])[N:9]=[C:10]([F:13])[C:11]=1[F:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)Oc1c(F)c(F)nc(F)c1Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)Oc1cc(F)nc(F)c1F
Reaction time: 22 h
Yield: 56470.9 %

Procedure:
To 4-t-butoxy-3-chloro-2,5,6-trifluoropyridine (24.92 g, 0.104 mmol) in 100 mL of methanol was added 2.5 g of Pearlman's catalyst (Aldrich Chemical Co.), and the mixture was stirred at ambient temperature for 14 hours under and atmosphere of hydrogen. An additional 2.5 g of catalyst was added, and the mixture was stirred for another 22 hours. The mixture was filtered, the filtrate was concentrated, and the residue was extracted with hexane/ether. After filtration, the solvent was removed by evaporation, and the residue was purified by flash chromatography (ethyl acetate:hexane 1:16) to yield 12.05 g of 4-t-butoxy-2,3,6-trifluoropyridine. MS 206 (M+H)+, 233 (M+18)+ ; 1H NMR (CDCl3)∂: 1.52 (s, 9H), 6.5 (m, 1H); 19F NMR (CDCl3, CFCl3 as reference)∂: 72.60 (dd, J1 =14.3, J2 =21.0 Hz), 89.74 (dd, J1 =14.3, J2 =21.0 Hz), 164.68 (dt, J1 =4.2, J2 =21.0 Hz).
Reaction SMILES: O=O.[K+].[C:4]1([O:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C1OCCOCCOCCOCCOCC[O:22]C1.O>CS(C)=O>[C:4]1([O:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:22])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: ClCCCCOc1cccc2ccccc12
Agent: O=O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: OCCCCOc1cccc2ccccc12

Procedure:
Potassium superoxide (0.71 g) was added to a solution of 4-(1-naphthyloxy)butyl chloride (2.0 g) and 18-Crown-6 (0.5 g) in dimethylsulfoxide (10 ml). After 8 hors the mixture was added to water and the solution was extracted with ether. The ethereal solution was dried and evaporated and the residue chromatographed on silica gel, eluting with 2:1 hexane ether, to yield the title compound as an oil.
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:10]([CH2:18][C:19]([CH2:21][O:22]C(=O)C2C=CC(OC)=CC=2)=[CH2:20])[C:9]1=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl>[Si:1]([N:8]1[C@@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:10]([CH2:18][C:19]([CH2:21][OH:22])=[CH2:20])[C:9]1=[O:33])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(COC(=O)c1ccc(OC)cc1)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: C=C(CO)C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1c1ccccc1
Reaction time: 2 h
Yield: 160.6 %

Procedure:
To a stirred mixture of (3S*,4R*)-1-tert-Butyldimethylsilyl-3-[2-(4-methoxybenzoyloxy)methyl-2-propenyl]-4-phenyl-2-azetidinone (18.74 g, 41.5 mmol), pH7 phosphate buffer (15.0 ml), and CH2Cl2 (250 ml) was added 2,3-dichloro-5.6-dicyano-1,4-benzoquinone (DDQ, 15.1 g, 66.4 mmol) portionwise at room temperature; on the addition, the reaction mixture became dark green, and then red solids precipitated with stirring. (In the course of addition, a slight heat evolution was observed.) The stirring was continued at room temperature for two hours, the reaction being monitored by TLC[Merck Kieselgel 60, n-hexane-AcOEt (3:1)]. sat. NaHCO3 aq. solution (80.0 ml) was added to quench the reaction, wherein gas evolution was observed. After Celite was added, the mixture was filtered through a pad of Celite, and the filter cake was washed with CH2Cl2. The combined filtrate and CH2Cl2 washings were washed with sat. NaHCO3 aq. solution (×2), and dried (MgSO4). The combined aqueous washings were filtered through a pad of Celite, and the filter cake was washed with CH2Cl2. From the combined filtrate and washings, the CH2Cl2 layer was separated, and the aqueous layer was extracted with CH2Cl2 (100 ml×3). The combined CH2Cl2 layer and washings were dried (MgSO4). The CH2Cl2 solution dried were combined, treated with activated charcoal, and concentrated in vacuo to give an orange oil (22.1 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 200 g). Elution with n-hexane-AcOEt (15:1/5:1/3:1) gave title compound (11.18 g, 81.2%) as a viscous pale yellow oil. IRmax (film): 3420(s), 1750(s), 1733(s), 1718(s), 1705(s), 1650(m), 1040(s), 900(s), 775(s) 700(s) cm-1 ; 1H-NMR δ: 7.43-7.25(m, 5H), 5.04(br.s, 1H), 4.82(br.s, 1H), 4.20(d, J=2.2 Hz, 1H), 4.06(br.s, 2H), 3.26(ddd, J=8.2, 7.0, 2.2 Hz, 1H), 2.67(dd, J=15.2, 7.0 Hz, 1H), 2.54(dd, J=15.2, 8.2 Hz, 1H), 2.42(br.s, 1H, OH), 0.92(s, 9H), 0.21(s, 3H), -0.19(s, 3H) ppm.
Reaction SMILES: Cl.[S:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:17]=2)=[CH:5][N:4]=[CH:3]1.[C:18](Cl)([Cl:20])=[O:19].C1(C)C=CC=CC=1.C(N(CC)CC)C>ClCCl>[S:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][N:13]([C:18]([Cl:20])=[O:19])[CH2:12][C:11]=3[CH:17]=2)=[CH:5][N:4]=[CH:3]1
Reactant: c1ncc(-c2ccc3c(c2)CNCCO3)s1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCOc2ccc(-c3cncs3)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 7-(thiazol-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride as obtained in step 2 in dichloromethane (20 mL) at −20° C. added 20% phosgene in toluene (0.25 mL, 0.50 mmol) followed by addition of triethylamine (0.35 mL, 25 mmol). The reaction was allowed to warm to 25° C. and stand for 18 h. The mixture was then concentrated to give 7-(thiazol-5-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carbonyl chloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11](=[S:25])[NH2:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: NC(=S)c1ccc(N2CCOCC2)cc1
Temperature: 70 °C
Yield: 83.4 %

Procedure:
To a solution of 4-morpholinobenzamide (4.91 g, 23.80 mmol) in THF (70 mL) was added Lawesson's Reagent (10.60 g, 26.20 mmol) with stirring. The mixture was heated at 70° C. for 4 h, then cooled to rt and concentrated in vacuo. CH2Cl2 (30 mL) and water (100 mL) was added to the residue. The mixture was then filtered and the filter cake was washed with water and dried to give the title compound as a yellow solid (4.41 g, 83.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:47]1[C:52](=[O:53])[CH2:51][CH2:50][C:48]1=[O:49])=[N+](C)C)C.CCN(C(C)C)C(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][N:47]2[C:52](=[O:53])[CH2:51][CH2:50][C:48]2=[O:49])=[O:31])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)O)cc(C(=O)OC(C)(C)C)c1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(OCCCCCCCCCC(=O)ON2C(=O)CCC2=O)cc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of 5-(9-Carboxy-nonyloxy)-isophthalic acid di-tert-butyl ester (156 mg, 0.34 mmol) in dry THF (2 ml) was added TSTU (125 mg) and DIPEA (0.08 ml). The mixture was stirred under nitrogen over night. The mixture was concentrated. The residue was redissolved in EtOAc and filtered. The filtrate was washed with 0.1N HCl (2×), and brine (1×), dried (Na2SO4) and concentrated to give a clear syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:5][CH:4]=1.[ClH:35]>CO>[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][C:17]([C:20]5[CH:21]=[C:22]([NH2:26])[CH:23]=[N:24][CH:25]=5)=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cncc(N)c4)cc2-3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(-c4cncc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine (0.39 g, 0.8 mmol) was dissolved in MeOH and treated with concentrated HCl (0.25 mL, 8 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 5-[6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine hydrochloride (0.21 g, 0.57 mmol) as yellow solid in 71% yield.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1cc2[nH]ccc2cn1
Product: CC(C)(C)OC(=O)Cn1ccc2cnccc21

Procedure:
The title compound is prepared from 1H-pyrrolo[3,2-c]pyridine as described in EXAMPLES 18 and 19, Part A using tert-butyl bromoacetate in place of methyl iodide. The crude product is purified by column chromatography eluting with a gradient of 3% MeOH/CH2Cl2 to 6% MeOH/CH2Cl2 to give the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:23](=O)[CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)(=[O:10])=[O:11])=[CH:3][C:2]=1[NH:1][CH2:23][CH3:24]
Reactant: CC=O
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Reaction time: 8 h

Procedure:
A round bottom flask was charged with methyl trans-4-(3-amino-4-chlorophenylsulfonamido)cyclohexamecarboxylate (Intermediate 10, 333 mg, 0.922 mmol) and acetaldehyde (52.1 μl, 0.922 mmol) followed by sodium triacetoxyborohydride (293 mg, 1.383 mmol) in DCE (9217 μl) and the reaction was stirred overnight. The reaction was diluted with DCM/sat'd NaHCO3, and the organic layer was separated and dried over MgSO4, then filtered and chromatographed on a Biotage 25S column to yield the title compound (224 mg, 0.598 mmol, 64.8% yield). Rf (50% EtOAc/heptane): sm=0.43; product=0.58. MS MH+=375.2
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1)#[N:2]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: COc1cc(C#N)ccn1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(CN)ccn1

Procedure:
A solution of 4-cyano-2-methoxypyridine (0.55 g, 4.1 mmol) in ethanol was hydrogenated at 60 psi H2 in the presence of 10% Pd/C (100 mg). After 3.5 h the catalyst was removed by filtration through Super-Gel and the liltrate evaporated to give the title compound as a foam.