Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Cr:6]([O-])([O-:9])(=[O:8])=[O:7].[Na+:11].[Na+].C(=O)=O.C(=O)(O)[O-].[Na+]>O>[OH2:2].[OH2:7].[Cr:1]([O:5][Cr:6]([O-:9])(=[O:8])=[O:7])([O-:4])(=[O:3])=[O:2].[Na+:11].[Na+:11]
Reactant: O=[Cr](=O)([O-])[O-]
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
For preparation of dichromate, there are mainly three production methods that have been industrialized. For example, in preparation of sodium dichromate, all of these methods employ sodium chromate solution as the starting material. In most countries, including China, a sulfuric-acid method is adopted, in which sodium chromate solution is acidified with sulfuric acid, as shown in 2Na2CrO4+H2SO4═Na2Cr2O7+Na2SO4, then concentrated by evaporation to precipitate sodium sulfate crystals that are then filtered out, and the filtrate is further concentrated by evaporation and then cooled to precipitate crystals, so as to afford the product sodium dichromate dihydrate. The chromate factories of Bayer AG (Germany) and of Corpus Christi, Tex., U.S. (both factories have been closed one after the other) used to produce sodium dichromate by an electrolysis method in which sodium chromate solution is fed into the anode chamber of an electrolytic tank having two chambers partitioned with an ion-exchange membrane, then electrolyzed into sodium dichromate under a direct current, and the liquid in the anode chamber is collected and evaporated to precipitate crystals to yield sodium dichromate dihydrate. Recently a similar method by the Qinghai Institute of Salt Lakes has also been published (see CN101481802A). A new chromate factory, built by Bayer AG (Germany) in Newcastle, South Africa, adopts a carbonation method in which sodium chromate solution is carbonated with pressurized carbon dioxide in a carbonation column, as shown in 2Na2CrO4+2CO2+H2O═Na2Cr2O7+2NaHCO3, most sodium bicarbonate is precipitated as crystals because of its low solubility and then filtered out at a decreased temperature with the partial pressure of carbon dioxide maintained, and the obtained sodium dichromate solution is adjusted in degree of acidification and then evaporated to precipitate crystals, so as to yield sodium dichromate dihydrate (see U.S. Pat. No. 5,250,274, 1993 for related techniques).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Br:11].Cl.[CH3:14][NH:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:15]([CH3:16])[CH3:14])=[CH:6][C:5]=1[Br:11]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1Br
Temperature: 70 °C
Reaction time: 11 h
Yield: 70 %

Procedure:
To a stirred solution of 5.24 g (22.5 mmol) 2-Bromo-4-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 11 h at 70° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 7a was obtained in 70% yield (4.08 g, 15.8 mmol).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].OS(O)(=O)=O.[CH3:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][CH:12]1O.[NH4+].[OH-]>C(Cl)Cl>[N:1]([CH:13]1[CH2:14][C:15]([CH3:18])([CH3:17])[CH2:16][C:11]([CH3:10])=[CH:12]1)=[N+:2]=[N-:3]
Reactant: CC1CC(C)(C)CCC1O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClCCl
Product: CC1=CC(N=[N+]=[N-])CC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44.2 %

Procedure:
To a cooled (0° C.) suspension of sodium azide (0.81 g, 12.5 mmol) in CH2Cl2 (5 ml) was added dropwise 53% aqueous H2SO4 (8 ml). The mixture was stirred for 10 min, then a solution of 3,5,5-trimethyl-2-cyclohexanol (33) (0.70 g, 5 mmol) in CH2Cl2 (8 ml) was added. The mixture was stirred for 20 h, poured into ice water, neutralized with aqueous NH4OH and extracted with CH2Cl2. The extract was washed with brine and dried over MgSO4. Filtration and evaporation of the solvent keeping the temperature below 25° C. gave an oil which was separated by column chromatography on silica gel (light petroleum ether). A fraction with Rf 0.8 (hexane) was collected. Evaporation of the solvent gave 34 as a colorless oil (0.365 g, 44%). 1H NMR (CDCl3, TMS): 0.89 and 1.01 (total 6H, both s, 5,5-CH3); 1.34 (1H, m, c-4-CH); 1.55-1.95 (3H, m, 4-CH, 6-CH2); 1.71 (3H, s, 1-CH3); 3.90 (1H, m, 3-CH) and 5.39 ppm (1H, s, C═CH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Cl-].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Fc1cccc(C[Zn+])c1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Cl-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3cccc(F)c3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-fluoro-benzylzinc chloride following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=523 [M+Na]+.
Reaction SMILES: [CH2:1](OC(OCC)CBr)[CH3:2].Br.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[C:18]([OH:24])=[N:19][CH:20]=[C:21]([CH3:23])[N:22]=1>CC(O)C.CCOCC>[CH3:23][C:21]1[N:22]2[CH:1]=[CH:2][N:16]=[C:17]2[C:18]([OH:24])=[N:19][CH:20]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1cnc(O)c(N)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cnc(O)c2nccn12
Reaction time: 8 h
Yield: 35.4 %

Procedure:
Bromoacetaldehyde diethyl acetal (12.2 mL, 81.4 mmol) and a solution of 48% HBr (0.94 mL) are heated at reflux for 1.5 hours, then poured into a suspension of NaHCO3 (1.92 g) in propan-2-ol (31.3 mL). The resulting solid is filtered off and 3-amino-5-methyl-pyrazin-2-ol (3.13 g, 25.0 mmol) is added. The solution is refluxed for 2 hours then left to stand overnight and the solid formed washed with IPA and ether. The solid is added to a solution of DCM (60 mL) and NaHCO3 sat. (30 mL), the two layers are separated and the aqueous phase is extracted with DCM. The combined organic layers are dried with MgSO4 anh., filtered and evaporated to give a brown solid product. The aqueous phase is again extracted with a CHCl3/IPA 9/1, dried with MgSO4 anh., filtered and concentrated to give a brown solid product. The IPA and Ether used previously for washing the solid are combined, evaporated and submitted to the same process described previously to give a brown solid quite impurified from the DCM extraction and a brown solid with the CHCl3/IPA of similar purity to the one obtained beforehand. The products resulting from the first DCM extraction and the two CHCl3/IPA extraction are combined and washed with cold MeOH to give 5-Methyl-imidazo[1,2-a]pyrazin-8-ol as a pale yellow solid (1.32 g) that is submitted into the next step without further purification.
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[N:19]1([C@@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31]3[C:36]([NH2:37])=[CH:35][N:34]=[C:33]4[CH:38]=[CH:39][S:40][C:32]=34)[CH2:26][CH2:25]2)[CH:23]=[N:22][CH:21]=[N:20]1>O1CCCC1.C(O)C>[N:19]1([C@@H:24]2[CH2:29][CH2:28][C@H:27]([N:30]3[C:31]4=[C:32]5[S:40][CH:39]=[CH:38][C:33]5=[N:34][CH:35]=[C:36]4[N:37]=[C:3]3[C@H:2]([OH:1])[CH3:6])[CH2:26][CH2:25]2)[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@@H](n2cncn2)CC1
Reactant: C[C@@H](O)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@@H](n2cncn2)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (28 mg, 0.32 mmol) and triethyloxonium tetrafluoroborate (60 mg, 0.32 mmol) in tetrahydrofuran (0.4 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of N7-[cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]thieno[3,2-b]pyridine-6,7-diamine (25 mg, 0.080 mmol) in ethanol (0.8 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.7 mg, 5.8%). LCMS calculated for C18H21N6OS (M+H)+: m/z=369.1. Found: 369.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]#[N:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]=1.C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:22][N:21]=[N:20][N:8]=2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2cc(Cl)sc2C#N)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(-c2cc(Cl)sc2-c2nnn[nH]2)cc1
Reaction time: 72 h
Yield: 265.8 %

Procedure:
A mixture of 5-chloro-3-(4-methylphenyl)thiophene-2-carbonitrile (4.67 g), trimethyltin azide (12.3 g) and xylene (100 ml) was heated under reflux for 15 hours. After standing for 3 days at ambient temperature, the precipitate was collected by vacuum filtration to give 5-chloro-3-(4-methylphenyl)-2-(1H-tetrazol-5-yl)thiophene (14.7 g) as a yellowish powder. This powder was treated with trityl chloride (6.7 g) and 10N aqueous sodium hydroxide (2.4 ml) in dichloromethane (59 ml), and tetrahydrofuran (10 ml) at ambient temperature for 20 hours. The reaction mixture was washed with brine and dried over magnesium sulfate. The solvents were evaporated in vacuo to give a residue which was purified by silica gel column chromatography to afford 5-chloro-3-(4-methylphenyl)-2-(1-trityl-1H-tetrazol-5-yl)thiophene (10.3 g).
Reaction SMILES: [N:1]([CH2:4][CH:5]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:13][C:7]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=1[CH:5]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(c1ccc(Cl)cc1Cl)N1CCCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: NCC(c1ccc(Cl)cc1Cl)N1CCCCC1

Procedure:
In a manner similar to Preparation 5 react 1-[2-azido-1-(2,4-dichlorophenyl)ethyl]piperidine with lithium aluminum hydride and aluminum chloride to obtain the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]3([C:23](O)=[O:24])[CH2:22][O:21][CH2:20]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:50][O:51][C:52]([C:54]1[C:55]([C:61]2[CH:66]=[CH:65][C:64]([C@H:67]([NH2:69])[CH3:68])=[C:63]([F:70])[CH:62]=2)=[CH:56][CH:57]=[CH:58][C:59]=1[Cl:60])=[O:53].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH3:50][O:51][C:52]([C:54]1[C:55]([C:61]2[CH:66]=[CH:65][C:64]([C@H:67]([NH:69][C:23]([C:19]3([NH:18][C:16]([O:15][CH2:14][CH:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[O:17])[CH2:22][O:21][CH2:20]3)=[O:24])[CH3:68])=[C:63]([F:70])[CH:62]=2)=[CH:56][CH:57]=[CH:58][C:59]=1[Cl:60])=[O:53]
Reactant: O=C(NC1(C(=O)O)COC1)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)N)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carboxylic acid (207 mg, 610 μmol, intermediate 8) in dry DMF (2.11 ml) were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (129 mg, 671 μmol) and 1-hydroxybenzotriazole hydrate (103 mg, 671 μmol) at room temperature. The colorless solution was stirred for 10 min before a solution of 4′-((R)-1-amino-ethyl)-3-chloro-3′-fluoro-biphenyl-2-carboxylic acid methyl ester hydrochloride (210 mg, 610 μmol) and triethylamine (61.7 mg, 85.0 μl, 610 μmol) in dry DMF (2.11 ml) was added. After addition, the brown solution was stirred at room temperature over night. Then water was added and the pH of the mixture was adjusted to 7 by addition of sat. NaHCO3 solution. The mixture was extracted three times with EtOAc and the combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 99:1-95:5) and the title compound was obtained as white solid (312 mg, 81%). MS: 629.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][C:7]1[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2cccc(OC)c2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cccc(Cc2nc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)no2)c1

Procedure:
This compound was prepared according to method F with ethyl 5-(3-methoxybenzyl)-1,2,4-oxadiazole-3-carboxylate (0.113 g; 0.433 mmol) in methanol (2 mL) and sodium hydroxide in water (2M, 2 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to 0.016 g (9%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(3-methoxybenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [C:1]1(=[O:14])[O:13][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][CH2:2]1.[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:19]=1[N:27]=[C:28]=[O:29])([CH3:17])[CH3:16].C([N-]C(C)C)(C)C.[Li+]>>[CH3:17][CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:25])[CH3:26])[C:19]=1[NH:27][C:28]([CH:2]1[CH2:3][CH2:4][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[O:13][C:1]1=[O:14])=[O:29])[CH3:16]
Reactant: CCCCCCCCC1CCC(=O)O1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCC1CCC(C(=O)Nc2c(C(C)C)cccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared from (±)-δ-dodecanolactone (5.0 g, 0.025 mol), 2,6-diisopropylphenyl isocyanate (5.12 g, 0.025 mol), and lithium diisopropylamide (0.025 mol) using the procedure described in Example 1.
Reaction SMILES: [CH3:1][N:2]1[C:10](=O)[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:10](=[S:34])[C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[N:4]2[C@H:19]3[CH2:24][CH2:23][CH2:22][C@H:20]3[N:21]=[C:3]12
Reactant: CN1C(=O)c2c(ncn2Cc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CN1C(=S)c2c(ncn2Cc2ccccc2)N2C1=N[C@@H]1CCC[C@@H]12

Procedure:
Treat cis-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylmethyl) cyclopenta[4,5]imidazo[2,1-b]purin-4(3H)-one (0.16 g=0.5 mmol) with Lawesson's reagent (0.2 g=0.5 mmol) in xylene overnight. Remove solvent and chromatograph on silica, eluting with 98:2 CH2Cl2 /MeOH to give the title compound as a yellow foam. FAB MS: M+1=338.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].Cl.[NH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[OH:20][CH:17]1[CH2:18][CH2:19][N:14]([C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:15][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-nitrobenzoyl chloride (10.0 g, 53.9 mmol) in DCM (10 ml) was added piperidin-4-one hydrochloride (10.96 g, 81.0 mmol) and triethylamine (22.53 ml, 162.0 mmol). The reaction mixture was stirred at room temperature for 30 min and evaporated to dryness. The crude material was treated with diethyl ether, solid obtained was filtered and dried under vacuum to give the title compound (9.0 gm).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O)(=O)C.[Na].C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:22])[O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH2:17][CH2:16]3)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(CN2CCc3cc(OC(=O)Nc4ccc(C(C)C)cc4)ccc32)cc1
Reaction time: 0.03 h
Yield: 81.6 %

Procedure:
To a solution of indolin-5-yl 4-isopropylphenylcarbamate (15.0 mg, 50.6 μmol) in 0.75 mL of dry dichloromethane was added 4-methoxybenzaldehyde (12.3 μL, 0.101 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 2 min, acetic acid (29 μL, 0.51 mmol) and sodium triacetoxyhydroborate (38 mg, 0.18 mmol) was added, successively. After the reaction mixture was stirred at the same temperature for 30 min, the reaction mixture was diluted with diethyl ether (2 mL). After the reaction mixture was neutralized by saturated NaHCO3 aqueous solution (1 mL), the organic layer was separated. The separated organic layer was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 50/50) to obtain the title compound as a white solid (17.2 mg, 82%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3[N:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:29][C:25]=3[C@@H:24]([NH:34]C(OC(C)(C)C)=O)[C@H:23]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=3[F:49])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]2[C:26]3[N:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[S:29][C:25]=3[C@@H:24]([NH2:34])[C@H:23]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:43]=3[F:49])[CH2:22][CH2:21]2)=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2sc(C(F)(F)F)nc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1c2sc(C(F)(F)F)nc2[C@H](OC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)CC[C@H]1c1cccc(F)c1F
Reaction time: 2 h
Yield: 89.8 %

Procedure:
(4R,7S,8S)-8-(tert-butoxycarbonylamino)-7-(2,3-difluorophenyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-4-yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (3.5 mg, 4.94 μmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (0.5 mL, 6.49 mmol) at rt. The reaction was stirred for 2 h. The solvent was removed under vacuum and the crude product was partitioned between sodium bicarbonate(sat.) and ethyl acetate. The organic layer was separated, dried (sodium sulfate), filtered and concentrated in vacuo. Flash chromatography, eluting with methanol in methylene chloride from 0 to 10% gave the desired product (2.7 mg, 90%) as a white solid: LCMS (M+Na=631.04).
Reaction SMILES: I[CH:2]([CH3:6])[CH:3](I)[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>CN(C)C=O>[C:18]([C:17]1([C:16]([O:15][CH2:13][CH3:14])=[O:26])[CH2:4][CH2:3][CH2:2][CH2:6]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(I)C(C)I
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)c2ccccc2)CCCC1
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Diiodobutane (17.1 g, 55 mmol), sodium carbonate (35 g, 330 mmol), ethylbenzoylacetate (10.6 g, 55 mmol) and dimethylformamide (170 ml) were mixed and the mixture was stirred at 55 to 60° C. overnight. The mixture after completion of reaction was poured into ice water and the mixture was extracted twice with ethyl acetate (100 ml). The extract was dried over sodium sulfate, and after concentration, purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (7.9 g, 58%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11](C1NC=CN=1)(C1NC=CN=1)=[S:12]>C(OCC)(=O)C>[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[C:11]=[S:12]
Reactant: COc1ccc(CN)cc1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: COc1ccc(CN=C=S)cc1
Yield: 153.3 %

Procedure:
To a stirred solution of 0.50 g (3.64 mmols) of the 4-methoxy-benzylamine (M) in 10 mL of ethyl acetate, was added 0.65 g (3.64 mmols) of thiocarbonyl diimidazole (N) portion wise. The resultant mixture was stirred at 50° C. for 10 min. then concentrated. The crude product was then dissolved in 15 mL of dichloromethane and passed through a short pad of silica gel using additional 50 mL of dichloromethane as eluent. Concentration of the filtrate afforded 1.0 g (87%) of (O) as white solid.
Reaction SMILES: CC([O-])=O.[NH4+].[BH3-][C:7]#[N:8].[Na+].[Br:10][C:11]1[C:12]2[CH2:19][CH2:18]C(=O)[C:13]=2[CH:14]=[N:15][CH:16]=1>CCO>[Br:10][C:11]1[C:12]2[CH2:19][CH2:18][CH:7]([NH2:8])[C:13]=2[CH:14]=[N:15][CH:16]=1
Reactant: O=C1CCc2c(Br)cncc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: NC1CCc2c(Br)cncc21
Reaction time: 0.07 h
Yield: 90.5 %

Procedure:
CH3COONH4 (4.8 g, 62 mmol), NaCNBH3 (315 mg, 5 mmol) and 4-bromo-5H-cyclopenta[c]pyridin-7(6H)-one (1.0 g, 4.15 mmol) in EtOH (10 mL) was added to a sealed microwave vial. The mixture was subject to microwave radiation at 130° C. for 4 min. After the majority of EtOH was evaporated under reduced pressure, it was treated with aq. 2 N NaOH until pH>10 and extracted with EtOAc (50 mL x2). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated under reduced pressure to give a crude title product (800 mg) which was used in the next step reaction without further purification. MS: 212.9 (M+H+, 1Br).