Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1.C[OH:32]>O>[F:7][C:8]1[CH:9]=[C:10]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:11]=[CH:12][C:13]=1[N:14]1[CH2:15][CH2:16][S:17](=[O:32])[CH2:18][CH2:19]1
Reactant: CO
Reactant: CC(=O)NCC1CN(c2ccc(N3CCSCC3)c(F)c2)C(=O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium metaperiodate (42 mg, 0.196 mmol) was dissolved in water (1 mL) and then cooled to 0° C. (ice bath). Next, the N-[[3-[3-fluoro-4-(4-thiomorpholinyl) phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (66 mg, 0.187 mmol) was added. Methanol (3 mL) was added to increase solubility. The reaction was stirred at 0° C. for an additional 4 hours under N2 before being stoppered and stored in the freezer (65 hours). The reaction was filtered through a medium-porosity sintered glass funnel, rinsing the flask and filter cake with CHCl3 (5 mL). The filtrate was transferred to a separatory funnel, the layers separated, and the water layer further extracted with more CHCl3 (3×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to yield 80 mg of a gummy solid. The material was chromatographed on silica gel (10 g silica, packed with 10% CH3CN/CHCl3), eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3 to give 49 mg (71%) of the title compound as an off-white solid with amp of 159°-161° C. and a HRMS (M+) calculated for C16H20N3O4FS 369.1158, found 369.1182.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=O)[CH2:14][CH3:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH3:15])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC=O
Reactant: c1ccc(C2CCCNC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CCCC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
3-Phenyl-piperidine (4.0 g, 24.81 mmol) and propionaldehyde (1.8 ml, 24.81 mmol) were dissolved in tetrahydrofuran (100 ml). Acetic acid (2.14 ml, 37.21 mmol) and sodium trisacetoxyborohydride (10.515 g, 49.61 mmol) were sequentially added to the reaction mixture and stirred for 1 hour at room temperature. The reaction mixture was concentrated and the residue was dissolved in aqueous NaHCO3 solution (50 ml) and diethyl ether (100 ml). The organic phases was dried over magnesium sulfate, filtered, and evaporated to dryness to yield the crude product (4.6 g, 87% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](S(C)(=O)=O)=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1.[CH3:41][Mg]Br.C(OCC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:41])=[N:9][C:8]=2[C:7]([C:20]#[N:21])=[C:6]1[N:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1
Reactant: C[Mg]Br
Reactant: Cn1c(S(C)(=O)=O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl {(3R)-1-[5-(2-chloro-5-fluorobenzyl)-7-cyano-3-methyl-2-(methylsulfonyl)-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (890 mg) in tetrahydrofuran (2 ml) was cooled to 0° C. and a 3M methylmagnesium bromide/diethyl ether solution (333 μl) was added dropwise thereto. After 30 minutes, the reaction solution was warmed to room temperature and stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (64 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CN(C=O)C.I[CH:19]([CH3:21])[CH3:20]>CCOC(C)=O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:19]([CH3:21])[CH3:20])[CH:12]=1
Reactant: CC(C)I
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(Br)cn1
Temperature: 25 °C

Procedure:
A sealable vessel was charged with potassium carbonate (3.76 g, 27.2 mmol), 4-bromo-1H-pyrazole (4.00 g, 27.2 mmol), and 10 mL DMF. To this mixture, 2-iodopropane (3.27 ml, 32.7 mmol) was added and the vessel sealed. The mixture was heated at 80 C for 16 h and allowed to cool to rt. The mixture was diluted with EtOAc, extracted with water, water, sat NaHCO3, and the organic layer dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a EtOAc in CH2Cl2 gradient. The desired compound (as determined by TLC, I2 stain) was collected as a colorless liquid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.I[CH:10]([CH3:12])[CH3:11]>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=1
Reactant: CC(C)I
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a slurry of sodium hydride (95%, 0.58 g, 23 mmol) in DMF (20 mL) was added a solution of 4-Iodo-1H-pyrazole (2023A) (4.07 g, 21 mmol) in DMF (20 mL) and the resulting mixture was stirred at rt for 10 min. Then 2-iodopropane (2.52 mL, 25.2 mmol) was added dropwise and the resulting mixture was stirred at rt overnight. The reaction mixture was concentrated, diluted with ethyl acetate, washed with water (4 times), brine, dried and concentrated to give an oily residue which was chromatographed (SiO2, 10%-20% ethyl acetate/hexane) to give 4-Iodo-1-isopropyl-1H-pyrazole 2023B (3.27 g, 66%). HPLC-MS tR=1.66 min (UV254 nm); mass calculated for formula C6H9IN2 235.98, observed LCMS m/z 237.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:25])[CH3:24])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O>CN(C)C=O>[Br:26][C:10]1[N:9]=[C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23](=[O:25])[CH3:24])[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCN([C@H]2CC[C@H](c3ncc4c(C)nccn43)CC2)CC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN([C@H]2CC[C@H](c3nc(Br)c4c(C)nccn43)CC2)CC1

Procedure:
To a stirred solution of 1-(4-((trans)-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)piperazin-1-yl)ethanone (0.422 mmol, 144 mg) in N,N-dimethylformamide (2 mL) was added N-bromosuccinimide (0.422 mmol, 75 mg). After two hours at 60° C. the reaction was quenched with a saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The organic extracts were washed twice with water and brine, dried (sodium sulfate) and concentrated under reduced pressure. The crude product was purified with column chromatography on silica gel (dichloromethane/methanol) to afford 176 mg of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)(C)(C)C.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19]>>[C:6]([CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:24]1[CH:25]=[CH:26][C:21]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=1)([OH:5])=[O:17]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by the method of example 1 step (ii) and step (iii) using the product from example 1 step (i) and 4-carboxyphenylboronic acid. Yield 0.035 g
Reaction SMILES: [C:1](Cl)(=O)C.[S:5]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:6]1=2>CO>[CH3:1][O:15][C:14]([C:13]1[C:6]2[S:5][CH:9]=[CH:8][C:7]=2[CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: O=C(O)c1cccc2ccsc12
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cccc2ccsc12
Yield: 92.7 %

Procedure:
Acetyl chloride (14.8 mmol; 1.05 mL) is added to a solution of benzo[b]thiophene-7-carboxylic acid (4.94 mmol; 880 mg) in methanol (20 mL). The reaction mixture is stirred at reflux for 24 h. The solvent is removed under reduced pressure. The residue is taken up in ethyl acetate washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the title compound (880 mg, 92%) as colorless oil. 1H NMR (CDCl3): δ 8.12 (dd, 1H, J=7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J=7.6 Hz, 1.2 Hz), 7.58 (d, 1H, J=5.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.41 (t, 1H, J=5.2 Hz), 4.03 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=2[N:12]=1.[CH3:19][C:20]1[C:28]2[CH2:27][O:26][C:25](=[O:29])[C:24]=2[CH:23]=[CH:22][C:21]=1[C@@H:30]1[CH2:32][O:31]1>CCO>[OH:31][C@H:30]([C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:29])[O:26][CH2:27][C:28]=2[C:20]=1[CH3:19])[CH2:32][N:6]1[CH2:5][CH2:4][N:3]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[N:12]=2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: N#Cc1ccc2sc(N3CCNCC3=O)nc2c1
Solvent: CCO
Product: Cc1c([C@@H](O)CN2CCN(c3nc4cc(C#N)ccc4s3)C(=O)C2)ccc2c1COC2=O
Temperature: 145 °C

Procedure:
A mixture of 2-(2-Oxopiperazin-1-yl)-1,3-benzothiazole-5-carbonitrile [I-8] (25 mg, 0.10 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (37 mg, 0.19 mmol) in EtOH (2 mL) in a 5 mL microwave tube was heated to 145° C. for 1.5 hours. LC showed formation of the title product, which was purified by silica gel flash chromatography. LC-MS (IE, m/z): 449 [M+1]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30].O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c(OC)c1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c(OC)c1
Yield: 87.9 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (100 mg, 0.24 mmol, prepared in Synthetic Example 24) in DMF (2 ml) was added hydrazine monohydrate (80%, 50 μl, 1.25 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (87 mg, 87%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]\[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C#Cc4ccc(F)cc4)cn3)c2CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(/C=C\c4ccc(F)cc4)cn3)c2CC1
Reaction time: 36 h
Yield: 63.1 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 1.9 mmol), Lindlar catalyst (240 mg), and quinoline (0.8 mL) in methanol (30 mL). Degas, purge with nitrogen, and stir under a balloon of hydrogen for 36 h. Filter the mixture and wash the catalyst with additional methanol. Concentrate the filtrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (8:1) to give (Z)-3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(4-fluoro-phenyl)-vinyl]-pyridin-2-ylmethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (630 mg, 63%). MS (APCI+) m/z: 525 (M+H), 425 (M+H−Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a pale yellow solid. MS (APCI+) m/z: 425 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:12]([C:13]#[N:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Br-].[CH2:16]([Zn+])[CH:17]([CH3:19])[CH3:18]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1CCCC1=O>[C:13]([C:12]1[C:2]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][CH:4]=[C:5]([CH:11]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:14]
Reactant: CC(C)C[Zn+]
Reactant: CCOC(=O)c1cnc(Cl)c(C#N)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1cnc(CC(C)C)c(C#N)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 145 mg (0.69 mmol) of ethyl 6-chloro-5-cyanonicotinate (from Step B), 1.65 mL (0.83 mmol) of isobutylzinc bromide (0.5 M in THF), and 100 mL of 1-methyl-2-pyrrolidinone was added 18 mg (0.03 mmol) bis(tri-tert-butylphosphine)palladium(0). After stirring at 65° C. overnight, the reaction mixture was cooled to rt and filtered through a cake of Celite. The filtrate was concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 75 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 0.99 (d, J=6.7, 6H), 1.43 (t, J=7.1, 3H), 2.27 (m, 1H), 2.99 (d, J=7.3, 2H), 4.45 (q, J=7.1, 2H), 8.50 (d, J=2.1, 1H), 9.28 (d, J=2.3, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[Cl:8][C:9]1[C:10]([F:16])=[C:11]([OH:15])[CH:12]=[CH:13][C:14]=1[Cl:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1cccc(Cl)c1F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(Cl)c(Cl)c1F
Reaction time: 24 h
Yield: 47.5 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of 3-chloro-2-fluorophenol (750 mg, 5.12 mmol) and N-chlorosuccinimide (684 mg, 5.12 mmol) in acetonitrile (30 mL) and the reaction mixture stirred for 24 h. The mixture was concentrated in vacuo and purified by chromatography on silica gel with heptane:EtOAc (9:1, v/v) as eluent to afford the title compound (440 mg, 48%) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7](CC#N)[CH2:6][S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2.Cl.[C:15]([OH:18])(=[O:17])[CH3:16]>>[O:1]=[C:2]1[CH:7]([CH2:16][C:15]([OH:18])=[O:17])[CH2:6][S:5][C:4]2[S:11][CH:12]=[CH:13][C:3]1=2
Reactant: CC(=O)O
Reactant: N#CCC1CSc2sccc2C1=O
Agent: Cl
Product: O=C(O)CC1CSc2sccc2C1=O
Temperature: 0 °C

Procedure:
To a solution of 25 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetonitrile in 100 ml of acetic acid is added 50 ml of concentrated hydrochloric acid and the mixture is refluxed under heating for 2 hours. Then, the mixture is poured into 500 ml of ice-cold water. The precipitated crystals are collected by filtration, washed with water and recrystallized from a mixed solvent of toluene and isopropyl ether to give 16.5 g of 4-oxo-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-acetic acid as white crystals, melting at 124°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Cl:10].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[CH2:6][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1Cl

Procedure:
Using 4-fluoro-3-chlorobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 155. 1H NMR(CDCl3): 7.42 (dd, 1H, J=7.0, 2.2 Hz), 7.27-7.20 (m, 1H), 7.12 (t, 1H, J=8.6 Hz), 6.32 (d, 1H, J=2.2 Hz), 6.21 (d, 1H, J=2.2 Hz), 4.23 (broad s, 2H), 3.67 (ABq, 2H, JAB=15.2 Hz), 3.57-3.48 (m, 1H), 3.38-3.30 (m, 2H), 3.19-3.08 (m, 1H), 3.05-2.90 (m, 4H), 2.65-2.55 (m, 2H), 2.02-1.88 (m, 2H). LRMS (ES)+: 404.4 (M+H)+.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][C:19](=S)[NH:20][N:21]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:25][NH2:26]>>[C:1]([NH:5][CH2:6][CH:7]([OH:23])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:21]=[N:20][C:19]([NH:25][NH2:26])=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(=S)[nH]n1
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione (2 g, 0.006 mole) and hydrazine hydrate (50 ml) was heated under reflux in an atmosphere of nitrogen for 90 minutes. Excess of hydrazine hydrate was removed under reduced pressure and 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine was isolated as the hemisulphate hemihydrate (2.34 g, 98%, m.p. 180°-185° ). Recrystallisation from aqueous ethanol gave a crystalline material of m.p. 200°-203° (decomposition). (Found: C, 52.41; H, 6.76; N, 17.78; M+, 331. C17H25N5O2. 1/2H2SO4. 1/2H2O requires: C, 52.43; H, 6.99; N, 17.98%; M(base), 331).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([OH:10])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1.IC.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]([O:10][CH3:22])=[CH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6]1
Reactant: CCOC(=O)c1cc(O)n(Cc2ccccc2F)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)n(Cc2ccccc2F)n1

Procedure:
21.58 g of ethyl 1-(2-fluorobenzyl)-5-hydroxy-1H-pyrazole-3-carboxylate 1-1-2 (81.66 mmol, 1.0 eq) were dissolved in dry acetone. Then 10.17 mL of iodomethane (163.3 mmol, 2.0 eq) and 40.63 g of potassium carbonate (294 mmol, 3.6 eq) were added. The precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was partitioned between DCM and water, the aqueous layer was separated and extracted with DCM twice. The combined organic layers were dried over magnesium sulfate, filtered off and concentrated in vacuo to give 14.74 g (52.96 mmol, 65%) of the crude target compound that was used for the next transformation without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C@@H:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][C@@H:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH3:37])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 2.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate, 1.18 g of (1S)-1-(2-chlorophenyl)ethanol, 3.33 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 2.3 g of di-tert-butyl azodicarboxylate in 60 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:39])=[C:16]([N:19]3[CH2:26][CH:25]4[CH:21]([C:22]([CH2:27][N:28]5C(=O)C6C(=CC=CC=6)C5=O)=[N:23][O:24]4)[CH2:20]3)[N:17]=2)[C:12](=[O:40])[C:11]([C:41]([OH:43])=[O:42])=[CH:10]1.O.NN>C(O)C>[NH2:28][CH2:27][C:22]1[CH:21]2[CH2:20][N:19]([C:16]3[N:17]=[C:18]4[C:13]([C:12](=[O:40])[C:11]([C:41]([OH:43])=[O:42])=[CH:10][N:9]4[C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:14][C:15]=3[F:39])[CH2:26][CH:25]2[O:24][N:23]=1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(CN5C(=O)c6ccccc6C5=O)C4C3)c(F)cc2c1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC1=NOC2CN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3F)CC12

Procedure:
Phthalimide 108 (241 mg; 0.409 mmol) and hydrazine hydrate (0.03 mL) in ethanol (5 mL) were heated at reflux temperature under a nitrogen atmosphere for 23 hours. After cooling, the thick reaction mixture suspension was filtered. The solid was washed with methylene chloride, water and dried to yield amine 200 as an off-white solid.
Reaction SMILES: COC1C=CC(S([O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:16]=2)(=O)=O)=CC=1.O[C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][O:12][C:34]3[CH:41]=[CH:40][C:37]([CH:38]=[O:39])=[CH:36][CH:35]=3)=[CH:16][CH:17]=2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COc1ccc(S(=O)(=O)OCCc2ccc(OS(=O)(=O)c3ccc(OC)cc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)Oc2ccc(CCOc3ccc(C=O)cc3)cc2)cc1
Yield: 101.4 %

Procedure:
A mixture of 8.5 g (17.8 mmole) 4-(4-methoxyphenylsulfonyloxy)phenethyl 4-methoxy-1-benzenesulfonate, 2.16 g (17.7 mmole) 4-hydroxybenzaldehyde and 10 g (72.5 mmole) potassium carbonate in 60 g acetonitrile was refluxed over night. The salt was filtered off and the solvent was evaporated. The crude product was purified on silica gel using dichloromethane as eluent to give 7.4 g of 4-[2-(4-formylphenoxy)ethyl]phenyl 4-methoxy-1-benzenesulfonate (slightly polluted with the corresponding styrene product).