Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C([Li])(C)(C)C.CCCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[C:19]([C:3]1[CH:4]=[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:9])[CH3:10])[CH:17]=[CH:18][C:2]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyi-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc—hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([C:17]4([C:20]5[CH:21]=[C:22]6[C:27](=[CH:28][CH:29]=5)[N:26]=[CH:25][CH:24]=[CH:23]6)[CH2:19][CH2:18]4)=[N:15][N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][O:31][C:32]1[N:33]=[CH:34][C:35]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[N:10][C:11]4[N:12]([C:14]([C:17]5([C:20]6[CH:21]=[C:22]7[C:27](=[CH:28][CH:29]=6)[N:26]=[CH:25][CH:24]=[CH:23]7)[CH2:19][CH2:18]5)=[N:15][N:16]=4)[N:13]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:36][CH:37]=1
Reactant: Brc1cccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)c1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2cccc(-c3cnc4nnc(C5(c6ccc7ncccc7c6)CC5)n4n3)c2)cn1
Temperature: 120 °C
Yield: 58.9 %

Procedure:
To a mixture of 6-{1-[6-(3-bromophenyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl]cyclopropyl}quinoline (16 mg, 0.036 mmol), 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (10 mg, 0.043 mmol), and potassium phosphate (30 mg, 0.14 mmol) in 1,4-dioxane (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (3 mg) and water (0.1 mL). The resulting mixture was heated at 120° C. overnight. The reaction mixture was cooled to RT and concentrated. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound 10 mg (60%). Analytical LCMS: (M+H)+=472.2.
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH3:9])([CH2:6][CH3:7])[C:3](=[O:5])[CH3:4].[Br:10]Br.[Cl-].[Al+3].[Cl-].[Cl-]>C(OCC)C>[Br:10][CH2:4][C:3](=[O:5])[C:2]([CH3:1])([CH2:8][CH3:9])[CH2:6][CH3:7]
Reactant: BrBr
Reactant: CCC(C)(CC)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CCC(C)(CC)C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 9.0 g of 3-methyl-3-ethyl-2-pentanone in 100 ml diethyl ether cooled to about 0°-5° C. with an ice bath was added 3.6 ml bromine. The reaction mixture was allowed to warm to room temperature and a catalytic amount of aluminum chloride was added. The mixture was stirred for 30 minutes and washed with water and a saturated sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under vacuum to provide an oil. The oil was distilled under vacuum to provide 6.3 g of product. bp=100°-114° C. at 16 mm.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([CH:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:26](=[O:33])[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:23])[CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>CO>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:26](=[O:33])[CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CC(C(=O)NN(CC(C)C)C(=O)CN1CCCC1)[C@H](CC=Cc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CN1CCCC1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.363 g of (E)-2(R)-([1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1-pyrrolidinyl)acetyl]valerohydrazide in 5 ml of methanol was treated with 0.133 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.317 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1-pyrrolidinyl)acetyl]valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([F:35])=[C:16]([C@:18]34[O:26][CH2:25][CH2:24][C@H:23]3[CH2:22][S:21][C:20]([NH:27]C(=O)OC(C)(C)C)=[N:19]4)[CH:17]=2)=[O:10])=[N:7][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:20]1[S:21][CH2:22][C@@H:23]2[CH2:24][CH2:25][O:26][C@:18]2([C:16]2[CH:17]=[C:12]([NH:11][C:9](=[O:10])[C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=3)[CH:13]=[CH:14][C:15]=2[F:35])[N:19]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)OCC[C@H]2CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]34N=C(N)SC[C@@H]3CCO4)c2)nc1
Yield: 146.8 %

Procedure:
A solution of tert-butyl ((4aR,7aR)-7a-(5-(5-cyanopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.012 mmol) and TFA (18.58 μL, 0.241 mmol) in DCM (121 μL) was stirred at rt for 3 h. The solvents were removed to give N-(3-((4aR,7aR)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-cyanopicolinamide (7 mg) as its TFA salt as a colorless oil. 1H NMR (500 MHz, CD3OD) δ 9.07 (1H, s), 8.46 (1H, dd, J=2.0, 8.0 Hz0, 8.37 (1H, d, J=8.0 Hz0, 8.17 (1H, dd, J=3.0, 7.5 Hz), 7.93 (1H, m), 7.25 (1H, dd, J=9.0, 11.0 Hz), 4.23 (2H, m), 3.43 (1H, m), 3.29 (1H, m), 3.15 (1H, m), and 2.31 (2H, m). MS (M+H)+: 398.1.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1

Procedure:
To a stirred solution of 4-fluoro aniline (16a, 4g, 32.7 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 6.69 g, 36.0 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl to afford compound N-(4-fluorophenyl)-4-nitrobenzamide (18a). To a stirred solution of amide (18a, 8g, 30.7 mmol) taken in toluene lawessons reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide) (10.18 g, 25.2 mmol) is added and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform finally purification by column chromatography to afford pure compound N-(4-fluorophenyl)-4-nitrobenzothioamide (19a). Treating the thioamide product (19a, 4g, 14.49 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 3h cyclization takes place to obtain the 6-fluoro-2-(4-nitrophenyl)benzo[d]thiazole (20a) solid is precipitated from the reaction mixture filtered and washed with water to get 20a. Reduction of the nitro compound (20a, 1 g, 3.64 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h. After completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21a) The compound 4-(6-fluorobenzo[d]thiazol-2-yl)benzenamine (21a, 244 mg, 1 mmol) on reaction with 4-fluoro 3-methoxy benzaldehyde (22c, 152 mg, 1 mmol) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product, and immediately proceeded for the next reaction with using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 4c as a light yellow solid (68%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12].[BH4-].[Na+]>CO>[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH:20][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Cl:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-4-fluoro-benzaldehyde (742 mg, 4.68 mmol) in MeOH (16 mL), add N-(2-aminoethyl)carbamic acid tert-butyl ester (500 mg, 3.12 mmol) and stir at RT for 4 hours. Cool reaction to 0° C. and slowly add NaBH4 (1.42 g, 37.4 mmol). Allow reaction to slowly warm to RT and stir for 12 hours. Quench reaction with 1N NaOH (80 mL) and extract with CH2Cl2 (40 mL). Dry organic layer over Na2SO4 and concentrate to afford the title compound. Quantitative yield. MS (IS) 303.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC([O-])=O.[Na+].[NH2:42][OH:43].Cl>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:42][OH:43])[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NO
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1cccc(F)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=NO)c1cccc(F)c1F
Temperature: 35 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of 1-(2,3-difluorophenyl)-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (21.1 g, 0.0435 mol, 1.0 equiv.) in MeOH (106 mL) was added NaOAc (5.36 g, 0.0653 mol, 1.50 equiv.) at ambient temperature. After 5 min., NH2OH HCl (3.33 g, 0.048 mol, 1.10 equiv.) was added in portions. The suspension was warmed to 35° C. and stirred for 1 h. The reaction mixture was cooled to 17.8° C. and stirred for 15 mins, then filtered and rinsed with EtOAc (84 mL). The filtrates were concentrated under vacuum (T<30° C.). To the resulting residue was charged 2-methoxy-2-methylpropane (169 mL) and water (21.1 mL). The organics were washed with sat. aq. NaHCO3 (53 mL) and 18% aq. NaCl (21 mL). The organics were concentrated under vacuum to afford the title compound as an oil (21.0 g). 1H NMR (500 MHz, CDCl3) δ ppm 7.42-7.32 (m, 6H), 7.30-7.15 (m, 10H), 7.16-7.06 (m, 1H), 7.03-6.95 (m, 1H), 5.72-5.58 (m, 1H), 5.24-5.13 (m, 2H), 4.80 (d, J=14.6 Hz, 1H), 4.73 (d, J=14.6 Hz, 1H), 4.45 (d, J=12.4 Hz, 0.3H), 4.35 (d, J=12.4 Hz, 0.3H), 3.99-3.91 (m, 0.3H), 3.91-3.83 (m, 1H), 3.20 (dd, J=9.9, 6.8 Hz, 0.3H), 3.09 (dd, J=9.8, 6.6 Hz, 1H), 3.02 (dd, J=9.9, 4.2 Hz, 0.3H), 2.95 (dd, J=9.8, 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ ppm 155.40, 150.59 (dd, JCF=248.1, 13.0 Hz), 148.86 (dd, JCF=252.6, 13.5 Hz), 143.96, 135.10, 128.73, 128.69, 127.72, 127.68, 126.92, 126.85, 124.96, 124.56 (d, JCF=10.6 Hz), 124.03-123.86 (m), 118.64 (d, JCF=15.1 Hz), 117.92 (d, JCF=17.2 Hz), 86.66, 86.50, 81.30, 80.32, 69.20, 66.54, 66.48, 62.57.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]1[O:17][CH:15]1[CH3:16]>C(O)C>[CH2:1]([N:8]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CO1
Reactant: CCC(O)CNCc1ccccc1
Solvent: CCO
Product: CCC(O)CN(Cc1ccccc1)CC(C)O
Temperature: 150 °C

Procedure:
To a solution of 1-benzylamino-butan-2-ol (Intermediate 482, 8.5 g, 47.48 mmol) in ethanol (150 mL) was added propylene oxide (8.8 g, 151 mmole) and the mixture was heated at 150° C. for 2 h in autoclave. After concentration of the mixture under reduced pressure, the residue was purified by column chromatography using methanol in dichloromethane to give product as an oil. Yield: 10.2 g (93%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+].O>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([O:10][CH2:11][CH3:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(N)cc(Cl)n1
Temperature: 150 °C
Yield: 87.8 %

Procedure:
To 2,6-dichloro-pyridin-4-ylamine (1.08 g, 6.6 mmol) in ethanol (1.5 mL) was added sodium ethoxide (2.5 M, 2.7 mL, 6.6 mmol) and the mixture was heated in a sealed tube at 150° C. for 6 h. Water was added, and the mixture was extracted with ethyl acetate. The extracts were concentrated and purified by silica gel flash column eluting with 30% ethyl acetate in hexanes to give the titled compound (1.0 g, 88%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1S(O)(=O)=O.C(N(CCCC)CCCC)CCC>ClCCl>[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1[S:20]([Cl:24])(=[O:22])=[O:21]
Reactant: Nc1c(C2CCCC2)cccc1S(=O)(=O)O
Reactant: O=S(=O)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: Nc1c(C2CCCC2)cccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.42 g (9.2 mmol) of triphenylphosphine in 5 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, 0.70 ml (8.8 mmol) of sulphuryl chloride. The reaction medium is left stirring for 10 minutes at 0° C., followed by addition over 5 minutes of a solution containing 1.06 g (4.4 mmol) of 2-amino-3-cyclopentylbenzenesulphonic acid and 1.04 ml of tributylamine in 3 ml of dichloromethane. The mixture is brought to room temperature and is left at this temperature for 2 hours, then it is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (1:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C)#[N:2].[NH4+].[Cl-].C([O:18]CC)C>C1COCC1.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:18])[CH2:6]2)#[N:2]
Reactant: CC1C(=S)Nc2ccc(C#N)cc21
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CC(=O)N2
Reaction time: 18 h

Procedure:
A solution of 5-cyano-3-methylthiooxindole (6.0 g, 29 mmol) in THF (100 mL) was stirred at room temperature and a saturated aqueous solution of NH4Cl (100 mL) added followed by activated zinc (25 g, 0.38 mol). The resulting mixture was stirred for 18 hours. The mixture was filtered through a pad of diatomaceous earth and the pad washed with THF (20 mL). The organic phase was separated, dried over anhydrous MgSO4 and the solvent evaporated to leave a tan solid. Trituration of this solid with diethyl ether gave 5-cyanooxindole a white solid, (4.1 g, 88%). 1H NMR (DMSO-d6) δ7.63 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 6.93 (d, 1H, J=8.4 Hz), 3.55 (s, 2H). MS (−ve ES) 157 (100), (M−H)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:4]=[N:3]1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1-c1sc(N)nc1-c1ccccc1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nc(-c2ccccc2)c(-c2nnnn2C)s1

Procedure:
Prepared from 5-(1-methyl-1H-tetrazol-5-yl)-4-phenyl-thiazol-2-ylamine and isobutyryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][Mg]Br.CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13](=[O:14])[N:12]3[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:11]3=[N:10][C:9]=2[CH:20]([OH:21])[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: Cc1cccc2nc(C=O)c(-c3cccc(F)c3)c(=O)n12
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc2nc(C(C)O)c(-c3cccc(F)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring suspension of 3-(3-fluorophenyl)-6-methyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine-2-carbaldehyde (1.3567 g, 4.806 mmol) in THF (48.06 mL) was added methylmagnesium bromide 3 M in Et2O (2.403 mL, 7.210 mmol) dropwise at 0° C. and the mixture was allowed to warm to rt and stirred at rt. After 5 h, the reaction was quenched with satd aq NH4Cl (50 mL) and water (50 mL) and extracted with EtOAc (50 mL×2). The combined organic layers were washed with water (50 mL×1), brine (50 mL×1), dried over Na2SO4, filtered, and concd under reduced pressure to give a dark red syrup. The dark red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min, then 50% isocratic of EtOAc in hexane for 10 min, 50 to 100% gradient of EtOAc in hexane over 10 min, and then 100% isocratic of EtOAc for 10 min as eluent to give 3-(3-fluorophenyl)-2-(1-hydroxyethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 (1 H, dd, J=8.8, 6.8 Hz), 7.41-7.52 (2 H, m), 7.12-7.24 (3 H, m), 6.88-6.96 (1 H, m), 4.98 (1 H, d, J=6.3 Hz), 4.42-4.51 (1 H, m), 2.89 (3 H, s), 1.26 (3 H, d, J=6.3 Hz); Mass Spectrum (ESI) m/e=298.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=[O:25])C.ClC1C=CC=C(C(OO)=O)C=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:11]3=[N+:12]([O-:25])[CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CN(C)C(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc[n+]([O-])c21
Temperature: 60 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-chlorophenyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-3-acetamide (0.3 g, 0.00096 mole), glacial acetic acid (2.5 ml), and m-chloroperbenzoic acid (0.66 g, 0.00384 mole) was heated at 60° C. for a total of 4 hrs. The reaction mixture was diluted with water and the organic acid which precipitated was filtered. The aqueous filtrate was neutralized for peroxides with 10% sodium sulfite. The aqueous solution was evaporated to dryness and the residue was dissolved in methylene chloride. The methylene chloride was extracted with a minimum of saturated sodium bicarbonate. The methylene chloride was dried and evaporated to a residue which crystallized upon standing. The solid was recrystallized from tetrahydrofuran-hexanes with refrigeration overnight. The solid was collected by filtration and dried under high vacuum overnight to give 0.28 g (88 %) of the title compound, mp 200°-201.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)c1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)c2ccccc2)nn1
Yield: 65 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using benzoyl chloride instead of methoxyacetyl chloride, to the title compound (250 mg, 65%) which was obtained as a white solid. MS: m/e=387.4 [M+H]−.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:15]2[CH:14]([S:16]([NH2:19])(=[O:18])=[O:17])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O.O>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:14]1([S:16]([NH2:19])(=[O:17])=[O:18])[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: NS(=O)(=O)C1c2ccccc2-c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(S(N)(=O)=O)c2ccccc2-c2ccccc21
Reaction time: 3 h
Yield: 25.2 %

Procedure:
To a stirred, 15° C. suspension of sodium hydride (60% in mineral oil, 500 mg, 12.2 mmoL, 1 eq) in 50 mL of dry dimethylformamide (from molecular sieves) under nitrogen was added dropwise over 15 minutes a solution of (8) (3 g, 12.2 mmoL) in 100 mL of dimethylformamide. A solution of ethyl bromoacetate (2.0 g, 12.2 mmoL, 1 eq) in 20 mL of dimethylformamide was then added dropwise over 10 minutes. After 3 h at room temperature, the reaction was diluted with water (100 mL), acidified (pH 5) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with brine (5×100 mL), dried (MgSO4), filtered and evaporated. The crude oil was purified by chromatography on silica gel using a gradient of 10%-30% ethyl acetate in hexane to provide 1 g (25%) of product: mp 167°-170° C., 1H NMR (CDCl3) 7.8-7.2 (m, 8H, aromatic protons), 3.9 (broad single, 2H), 3.6 (s, 2H), 3.5 (q, 2H), 1.7 (t, 3H).