Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:14]=2[C:15]=1[NH2:16])(=[O:10])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CC(O)=O.OP(O)(O)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:13]2[O:12][C:11]3[C:1](=[O:10])[CH2:2][CH:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:16][C:15]=3[C:14]=2[CH:17]=1
Reactant: Nc1c(C(=O)/C=C\c2ccccc2)oc2ccc(Br)cc12
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(c2ccccc2)Nc2c1oc1ccc(Br)cc21
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (28 g, 81.83 mmol) in AcOH (70 mL) and H3PO4 (70 mL) was refluxed for 2 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into water (250 mL) The yellow solids precipitated out were collected by filtration to give 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C) (23.8 g, 85% yield).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6](OC)=O)#[N:4].[Br:10][C:11]1[CH:18]=C[C:14]([C:15]#[N:16])=[C:13](F)[CH:12]=1.Cl>CS(C)=O.O>[Br:10][C:11]1[CH:18]=[CH:6][C:5]([C:3]#[N:4])=[C:13]([CH2:14][C:15]#[N:16])[CH:12]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0° C. in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4-Bromo-2-fluorobenzonitrile (118 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 90° C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104° C. over 3 hours. 2.3 L of water were added, and the mixture was heated at reflux 16 hours. The mixture was cooled to 5° C. HCl (700 mL, 0.2 N) was added, and the mixture was allowed to stir at 5° C. for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78%). LCMS (API-ES) m/z: 223, 221 (M+H+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](OCC)=[O:20])=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: OC/C=C/c1ccc(Br)cc1

Procedure:
The colourless solid (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4-bromo-phenyl)-acrylate (example 71a) as described for example 52b.
Reaction SMILES: [N:1]1([C:6]2[N:22]=[C:9]3[CH:10]=[C:11]([NH:14]C(=O)OC(C)(C)C)[CH:12]=[CH:13][N:8]3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>ClCCl>[N:1]1([C:6]2[N:22]=[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][N:8]3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Agent: Cl
Solvent: ClCCl
Product: Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.2 %

Procedure:
A mixture of tert-butyl 2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamate (340 mg, 1.12 mmol) and hydrochloric acid (5N in ether, 25 ml, 125 mmol) in dichloromethane (10 ml) was stirred for 20 hours at 25° C. The solvent was evaporated, the residue was triturated with sat. sodium hydrogencarbonate solution, the solid was filtered off, washed with water several times and dried affording 2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (194 mg, 85.2%) as a light yellow solid. mp: 221-225° C., MS: m/z=204.4 (M+H+)
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH3:26])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH3:26][O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24]
Reactant: COC(=O)c1ccccc1N
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)[C@H]1CC[C@H](CNC(=N)N)CC1

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and methyl anthranilate (2.3 g, 0.015 mole) are added to pyridine (20 ml), and the mixture is stirred for a while, and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to dryness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give the title compound (2.23 g) as white crystals. m.p. 118.5°-120.5° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=1)[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O=[Pt]=O.CO>[CH:2]1([CH2:1][CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccnc(Cc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1CCNC(CC2CCCCC2)C1
Reaction time: 72 h

Procedure:
Methyl 2-benzylisonicotinate (1.29 g, 5.67 mmol) and PtO2 (0.13 g, 0.57 mmol) were added to acetic acid (50 mL). The reaction mixture was hydrogenated in a Büchi hydrogentor at 8 bar at room temperature for 3 days. Methanol (100 mL) was added and the catalyst filtered off. The solvent was evaporated. The crude product was partitioned between Na2CO3 (aq) and ethyl acetate. The organic phase was isolated, dried over Na2SO4, filtered through Celite® and the solvent was evaporated. 1H NMR (600 MHz, cdcl3) δ 0.78-0.91 (m, 2H), 1.04-1.27 (m, 5H), 1.27-1.38 (m, 1H), 1.48 (ddd, 2H), 1.63 (dd, 5H), 1.80-1.93 (m, 2H), 2.36 (tt, 1H), 2.51-2.57 (m, 1H), 2.61 (td, 1H), 3.11 (ddd, 1H), 3.64 (s, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH2:23])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(CC)CC>CCO>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH2:12][C@@H:11]([NH:23][C:29]2[CH:30]=[C:25]([Cl:24])[N:26]=[CH:27][N:28]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 140 °C
Yield: 57.2 %

Procedure:
To a solution of (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentanamine (0.400 g, 1.11 mmol) in EtOH (3.0 mL) was added 4,6-dichloro-pyrimidine (0.199 g, 1.33 mmol) and Et3N (0.310 mL, 2.22 mmol). The reaction was heated to 140° C. for 1 h in a sealed tube using microwave irradiation then concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (CH2Cl2) to afford the title compound (0.300 g, 57%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:22][CH2:23][CH2:24][Cl:25].C1(C)C=CC=CC=1>CCOCC.CCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Reactant: ClCCCBr
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: ClCCCN1c2ccccc2CCc2ccccc21
Reaction time: 12 h

Procedure:
A solution of 10,11-dihydro-5H-dibenz[b,f]azepine (19.5 gms.; 0.10 moles) in dry ether was added to a solution of 7.7 gms. (0.12 mole) of butyl lithium in hexane. The stirred solution was warmed for approximately one hour and then 31.0 gms. (0.20 mole) of bromopropylchloride in ether was added and the resulting mixture heated at reflux for 16 hours. Aliquot analysis showed no reaction had taken place. Approximately one liter of toluene was added to the reaction mixture, lower boiling solvents were removed by distillation and the reaction mixture heated at reflux with stirring for 12 hours. On working up the reaction mixture, there was obtained 7.0 gms. of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine which distilled at 150°-153°C. (0.03 mm.). An additional 6.0 gms. of impure material which contained approximately 15% of unreacted 10,11-dihydro-5H-dibenz[b,f]azepine was obtained which distilled at 140°-150°C. (0.03 mm.).
Reaction SMILES: C(O[C:4]([CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1)=[O:5])C.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:4]([CH:6]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[S:7]2)=[O:5])=[CH:21][CH:20]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C1Sc2ccccc2N(C)C1=O
Product: CN1C(=O)C(C(=O)Nc2ccc(F)cc2)Sc2ccccc21
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A mixture of 2-ethoxycarbonyl-4-methyl-2H-1,4-benzothiazin-3(4H)one (2.4 g) and 4-fluoroaniline (1.59 g) was stirred for 5 hours at 180° to 185° C. After standing at room temperature, the reaction mixture was crystallized from diisopropyl ether and purified by recrystallization from diisopropyl ether to afford 0.94 g of 2-(4-fluorophenylcarbamoyl)-4-methyl-2H-1,4-benzothiazin-3(4H)one as a white crystal.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][CH2:25][S:26](Cl)(=[O:28])=[O:27].O>C1COCC1.CCCCCC>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3=[N:20][S:26](=[O:28])(=[O:27])[CH2:25][CH2:24][N:16]3[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)pyridin-2-amine (47 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 35.8 mg) and 2-chloroethanesulfonyl chloride (88 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (53.2 mg) as a white solid. The obtained solid was crystallized from THF and diisopropyl ether to give a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:32])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=4)[CH:17]=3)[S:12][C:11]([CH3:32])([CH3:33])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (940.0 mg, 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d6-acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, q, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound, the final desired product, was termed VTP 194310.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=[C:7]([NH2:9])[N:8]=1.[C:14]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O:16][CH3:17])=[O:15]>C(#N)C>[CH3:1][O:2][C:3]1[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=[C:7]([NH:9][C:27]([NH:26][S:23]([C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:24])=[O:25])=[O:28])[N:8]=1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Reactant: COc1nc(N)nc2oc(C)cc12
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(OC)c2cc(C)oc2n1

Procedure:
A 0.2 g sample of 4-methoxy-6-methylfuro[2,3-d]pyrimidin-2-amine of Example 8 was stirred in 10 ml of anhydrous acetonitrile while 2.0 ml of a 1M solution of 2-carbomethoxy-3-thiophenesulfonylisocyanate in acetonitrile was added at once. The mixture immediately became homogenous then the solid product crystallized out at ambient temperature and was collected after 1 hour. The yield of product was 0.3 g, m.p. 194°-196°. An NMR (60 MHz) spectrum (CDCl3 /DMSO-d6) exhibited absorptions at 2.5, 4.2, 6.4, 7.3, 7.9, 3.9 (methyl ester), 7.5 and 12.5 (broad NH's) ppm and the infrared spectrum (nujol) exhibited bands at 3100 (NH), 1730 (ester), 1700 (urea) cm-1 indicating the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:18][CH3:19])=[N:6][C:7]2[N:8]([CH:11]=[C:12]([C:14]([NH:16][NH2:17])=[O:15])[N:13]=2)[C:9]=1[CH3:10])[CH:2]=[CH2:3].[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH2:1]([C:4]1[C:5]([O:18][CH3:19])=[N:6][C:7]2[N:8]([CH:11]=[C:12]([C:14]3[O:15][C:20]([CH3:21])=[N:17][N:16]=3)[N:13]=2)[C:9]=1[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)nc2nc(C(=O)NN)cn2c1C
Reactant: CCOC(C)(OCC)OCC
Product: C=CCc1c(OC)nc2nc(-c3nnc(C)o3)cn2c1C

Procedure:
A mixture of 3.58 g of 6-allyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbohydrazide and 25 cm3of triethyl orthoacetate was heated at 150°-180° C. for 16 hours. The mixture was then cooled and evaporated to dryness and the resulting crude product purified by flash chromatography to obtain 1.47 g of 6-allyl-7-methoxy-5-methyl-2-(5-methyl-1,3,4-oxadiazol-2-yl)imidazo[1,2-a]pyrimidine.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4].C(Cl)Cl.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[C:23]([O:1][CH2:2][C@H:3]([N:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[C:11]=2[N+:15]([O-:17])=[O:16])[C:6]1=[O:19])[CH3:4])(=[O:25])[CH3:24]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(1-hydroxypropan-2-yl)-6-methyl-5-nitroisoquinolin-1 (2H)-one (4.8 g, 0.018 mol) in methylene chloride (100 mL, 2 mol) was added acetic anhydride (7 g, 0.07 mol), triethylamine (10 g, 0.1 mol) and 4-Dimethylaminopyridine (20 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 hour, washed with 1N hydrochloric acid and brine, and dried. The volatiles were removed under reduced pressure and the residue was purified by column chromatography to afford a yellow-brown oil.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][CH:45]=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH2:41][CH2:40]2)C1C=CC=CC=1>CO.[Pd]>[CH2:56]([C:53]1[CH:52]=[CH:51][C:50]([CH2:49][C:46]2[CH:47]=[C:48]3[C@:10]4([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]4)[CH2:40][CH2:41][O:42][C:43]3=[CH:44][CH:45]=2)=[CH:55][CH:54]=1)[CH3:57]
Reactant: CCc1ccc(Cc2ccc3c(c2)[C@]2(CCO3)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Cc2ccc3c(c2)[C@]2(CCO3)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 3 h

Procedure:
(2′S,3′R,4′S,5′R,6′R)-3′,4′,5′-Tris(benzyloxy)-6′-(benzyloxymethyl)-6-(4-ethylbenzyl)-3′,4′,5′,6′-tetrahydrospiro[chroman-4,2′-pyran] (11) (13.4 mg (0.018 mmol) was dissolved in MeOH (1 mL). Pd/C (5 mg, 10% Pd/C) was added, the reaction vessel was flushed with H2, (3×, alternating with high vacuum), then stirred under an atmosphere of H2. After 3 h, additional Pd/C (5 mg) was added and the vessel flushed again with H2 (3×, alternating with high vacuum), and the reaction mixture was stirred for an additional 16 h. The crude mixture was concentrated onto celite and chromatographed over SiO2 (ISCO system, 0-20% MeOH/CH2Cl2) to provide two fractions, with 1.7 and 6.3 mg respectively. (8 mg total, >100%). The smaller fraction was of the highest purity and was submitted for biological analysis. (The second fraction had slightly dark color, indicating some Pd contamination.) For the pure fraction: 1H NMR (300 MHz, CDCl3) δ ppm: 7.22 (m, 2H), 6.99-7.11 (m, 5H), 6.77 (d, J=8.1 Hz, 1H), 4.27-4.33 (m, 1H), 4.04-4.11 (m, 1H), 3.59-3.97 (m, 6H), 2.60 (q, J=15, 7.5 Hz, 2H), 2.37-2.46 (m, 1H), 2.12 (m, 1H), 1.21 (t, J=7.5 Hz, 3H). LC/MS 98.4% (ELSD) tR=1.80 min, calcd for C23H28O6: 400.19, found 423.0 (M+Na)+.
Reaction SMILES: C1(=O)NC(=O)C2=CC=CC=C12.[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]2C(=O)C3C(=CC=CC=3)C2=O)[CH:16]=[CH:15][CH:14]=[N:13]1.NN.Cl>CO>[N:12]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCn1cccn1
Agent: Cl
Agent: NN
Agent: O=C1NC(=O)c2ccccc21
Solvent: CO
Product: NCCCCCn1cccn1

Procedure:
A mixture of the phthalimide such as 2-[5-(1H-1-pyrazolyl)pentyl]-1,3-isoindolinedione and hydrazine (one equivalent) in methanol were heated to reflux temperature for 12 hours and cooled. 1 N HCl (1-5 equivalents) was added and the mixture was filtered and washed with methanol and water and then concentrated to give 5-(1H-1-pyrazolyl)-1-pentanamine as a viscous oil. (Scheme 1G)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([OH:14])[CH2:8][CH2:7]2)[CH3:2].[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][N:19]=1>C1COCC1.CCOCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([O:14][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=1)[CH2:8][CH2:7]2)[CH3:2]
Reactant: Clc1ncnc2ccccc12
Reactant: CCOc1ccc2c(c1)CCC(O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1)CCC(Oc1ncnc3ccccc13)C2
Temperature: 25 °C

Procedure:
2.57 g (13.3 mmol) of 6-ethoxytetralin-2-ol in 5 ml of THF were added, with ice-cooling, to a suspension of 400 mg of NaH (80% pure, 13.3 mmol in 40 ml of THF). The mixture was subsequently refluxed for 1 hour and cooled to room temperature, and 2.0 g (12.2 mmol) of 4-chloroquinazoline were added. The mixture was refluxed for 24 hours and cooled and then diluted with ether and washed with saturated sodium hydrogen carbonate and saturated sodium chloride solution. After the organic phase had been dried and concentrated, the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (9:1, 8:2). This gave 2.39 g (61% of theory) of colorless crystals (m.p.115-117° C.).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:26]([F:38])=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[C:26]([F:38])=[C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(Cl)c2F)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-chloro-2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.321 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.066 g (40% yield) of pure product: MS (ES) m/z 530 (M+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:26][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C@@H:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(Br)s2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
A suspension of 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (1.0 g, 2.64 mmol) and N-bromosuccinimide (470 mg, 2.64 mmol) in carbon tetrachloride (5 mL) at 25° C. was treated with benzoyl peroxide (32 mg, 0.132 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred at this temperature overnight. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (60 mL). The organic phase was then washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 to 1/1 hexanes/ethyl acetate) afforded N-(5-bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (546 mg, 45%) as an amorphous solid: EI-HRMS m/e calcd for C18H21BrN2O3S2 (M+) 456.1077, found 456.1077.