Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16](=O)[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].CO.C([BH3-])#[N:22].[Na+]>>[NH2:22][CH:16]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:2]([Br:1])[CH:3]=1)[CH3:17]
Reactant: CC(=O)c1ccc(C(=O)N2CCOCC2)c(Br)c1
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc(C(=O)N2CCOCC2)c(Br)c1

Procedure:
To a solution of the compound yielded from step 4 (160 mg, 0.51 mmol) in MeOH (3 mL) ammonium acetate (395 mg, 5.13 mmol) and sodium cyanoborohydride (32 mg, 0.513 mmol) were added. The reaction mixture was refluxed for 3 h. Then the mixture was quenched by addition of trifluoroacetic acid (pH=2) and evaporated to dryness. Purification of the crude product by prep-HPLC and lyophilization of the relevant fractions leads to the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH2:38]([NH:40][CH2:41][CH2:42][OH:43])[CH3:39]>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:40]([CH2:38][CH3:39])[CH2:41][CH2:42][OH:43])(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH2:27][CH3:28])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Reactant: CCNCCO
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCc1nc(CC)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N(CC)CCO)ccc3OCC)nn12
Temperature: 0 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
0.64 g (1.5 mmol) of 4-ethoxy-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of dimethylaminopyridine, 0.40 g (4.50 mmol) of 2-(ethylamino)-ethanol are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Chromatography (dichloromethane/methanol=95:5) gives 0.454 g (63%) of a colourless solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:26])[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3([CH3:26])[CH2:25][CH2:24][CH:23]=[CH:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC=CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)CC=CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoate (0.041 g, 0.11 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo to afford 5-cyclopropyl-2-fluoro-4-((1-methylcyclohex-3-en-1-yl)methoxy)benzoic acid (0.033 g, 0.11 mmol) which was used directly in the next step. This compound was dissolved in tetrahydrofuran (2 mL) under an atmosphere of nitrogen and carbonyldiimidazole (0.024 g, 0.15 mmol) was added to the solution and the reaction mixture was stirred at 70° C. for 1 hour. The mixture was cooled to ambient temperature and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.04 mg, 0.17 mmol) was added, followed by cyclopropanesulfonamide (0.021 mg, 0.170 mmol) and stirring continued at ambient temperature for 18 hours. 5% aqueous hydrochloric acid solution (0.15 mL) was added and the mixture was concentrated and purified by column chromatography (0 to 30% ethyl acetate in hexanes) to afford the title compound (0.012 g, 24%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.18-8.28 (br, 1H), 7.60 (s, 1H), 6.56 (d, J=14.4 Hz, 1H), 5.75-5.57 (m, 2H), 3.76 (d, J=8.5 Hz, 1H), 3.69 (d, J=8.6 Hz, 1H), 3.17-3.00 (m, 1H), 2.18-1.95 (m, 4H), 1.95-1.81 (m, 1H), 1.78-1.63 (m, 1H), 1.57-1.36 (m, 3H), 1.23 (s, 3H), 1.18-1.05 (m, 2H), 0.96-0.85 (m, 2H), 0.68-0.59 (m, 2H); MS (ES+) m/z 408.2 (M+1); MS (ES−) m/z 406.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[O:19][CH3:20].[C:21](OC(=O)C)(=O)C>CN(CN(C)C)C>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=[CH:5][C:6]=1[C:9](=[O:18])[C:10]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[CH2:21]
Reactant: COc1ccc(C(=O)Cc2ccc(Br)cc2)c(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,3-dichloro-4-(4-bromophenyl)acetyl anisole (142.5 g., 0.38 mole) in bis-dimethylaminomethane (325 ml.) under nitrogen is added dropwise acetic anhydride (325 ml.) with cooling to maintain the reaction mixture temperature below 40° C. The reaction mixture is stirred at 25° C. for one hour, then poured into crushed ice-water (4 l.) to precipitate 143 g. of 2',3'-dichloro-4'-methoxy-2-(4-bromophenyl)acrylophenone which melts at 110°-116° C. after crystallization from benzene:hexane, 1:5.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[C:21]1[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=[C:19]([F:30])[CH:20]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cc(F)ccc4F)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.73 g, 44%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,5-difluorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.22 g, 0.51 mmol) and methylamine (0.155 g, 5.1 mmol). mp 185-187° 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[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH2:56][C:57]1[O:61][N:60]=[C:59]([CH:62]([CH3:64])[CH3:63])[CH:58]=1>CN(C=O)C>[CH:62]([C:59]1[CH:58]=[C:57]([CH2:56][NH:55][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[O:61][N:60]=1)([CH3:64])[CH3:63]
Reactant: CC(C)c1cc(CN)on1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCc2cc(C(C)C)no2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 5-aminomethyl-3-isopropylisoxazole (1 M solution in trifluoroacetic acid, 354 μL, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (112 mg, 81%) which was obtained as a colourless gum. MS: m/e=433.3 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C([Li])CCC.[C:25](Cl)(=[O:27])[CH3:26]>C1COCC1>[C:25]([N:12]1[C@H:8]([CH2:7][C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:6][CH:5]=2)[CH2:9][CH2:10][C:11]1=[O:13])(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)CC[C@H]1Cc1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(S)-5-biphenyl-4-ylmethylpyrrolidin-2-one (1-a, R1=H) (5 g, 19.9 mmol) is dissolved in THF (50 ml). The mixture is cooled to −78° C. and n-butyllithium (14 ml, 1.6 M) added. After 0.5 h, acetyl chloride (1.7 ml, 24 mmol) is added and the mixture is allowed to warm to room temperature. After 1 h, the mixture is quenched with saturated ammonium chloride (40 ml) and water (10 ml) and ethyl acetate (20 ml) are added. The organic phase is washed with brine, dried (MgSO4) and concentrated in vacuo to give (S)-1-Acetyl-5-biphenyl-4-ylmethyl-pyrrolidin-2-one (1-a, R1=Ac). 1H NMR (CDCl3): 1.84 (1H), 1.93 (1H), 2.30 (1H), 2.32 (1H), 2.50 (3H), 2.72 (1H), 3.09 (1H), 4.56 (1H), 7.20 (2H), 7.28 (1H), 7.37 (2H), 7.49 (4H).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)[CH:2]=[CH2:3].C([O-])(=O)C.[Na+].Cl.[NH2:24][OH:25]>C(O)C>[CH2:1]([N:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[N:24][OH:25])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)CC(=O)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
2-(Diallylamino)-1-(4-fluorophenyl)ethanone (13.38 g, 57.36 mmol) is dissolved in ethanol (250 mL) and sodium acetate (5.7 g) is added followed by hydroxylamine hydrochloride (5.23 g, 74.6 mmol). The reaction is warmed to 70° C. for 2.5 hours then stirred at room temperature for 16 hours. The mixture is concentrated and the resulting residue is purified by silica gel flash chromatography eluting with ethyl acetate/hexanes (gradient 0-100%). The isolated material is repurified a second time to give the title compound (7.76 g, 54.5%). ES/MS (m/e): 249 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]Cl)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Reactant: CC(=O)N1CCN(CCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (250 mg, 0.74 mmol), 1-acetyl-4-(2-chloroethyl)piperazine (144 mg, 0.81 mmol) and potassium carbonate (112 mg, 0.81 mmol) in N-methylpyrrolidinone (6 ml) was heated at 90° C. for 2 hours. The mixture was cooled and water added. After 30 minutes the solid was filtered off and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (310 mg, 58%) as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1Cl)=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:25][CH2:26][CH3:27])(=O)C>O1CCOCC1.COC1C(N)=CC=CC=1>[C:1]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:11][C:10]1[CH:9]=[CH:1][CH:2]=[CH:27][C:26]=1[O:25][CH3:22])=[CH:16][CH:15]=[CH:14][C:13]=2[O:20][CH3:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)c(C(=O)c3ccccc3)cnc12
Reactant: CCOC(C)=O
Solvent: C1COCCO1
Solvent: COc1ccccc1N
Product: COc1ccccc1Nc1c(C(=O)c2ccccc2)cnc2c(OC)cccc12
Yield: 61 %

Procedure:
3-Benzoyl-4-chloro-8-methoxyquinoline (2.8 g, 0.0094 mol) was heated under reflux in a mixture of 1,4-dioxan (50 ml) and o-anisidine (7 ml) for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane, and washed with dilute hydrochloric acid sodium hydrogen carbonate solution, water and brine. The organic solution was dried and evaporated to an oil which was chromatographed (silica gel, 1% methanol in dichloromethane) to give an oil which afforded yellow crystals of 3-benzoyl-4-(2-methoxyphenylamino)-8-methoxyquinoline (2.2 g, 61%) from ethyl acetate, m.p. 200°-202°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1cc(Cl)ccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.6 %

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) and ethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (80 mL 1.0 M in tetrahydrofuran, 80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Upon complete addition, the cold bath was removed and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and methanol was added to the reaction, resulting in the formation of a white precipitate. The precipitate was collected by filtration and dried to give 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as a white solid. 1H-NMR (DMSO-d6): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s, 1 H), 5.67 (s, 1H), 4.14 (m, 2H); 19F-NMR (DMSO-d6): δ −115.67; MS m/z 250 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[CH2:9]([NH:1][CH2:2][CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CNCCc2cnc[nH]2)cc1
Reaction time: 3 h
Yield: 82.8 %

Procedure:
A solution of histamine (free base) (1.00 g, 9.0 mmol) and benzaldehyde (0.91 mL, 9.0 mmol) in MeOH (25 mL) was stirred at rt for 30 min. To this solution was slowly added NaBH4 (0.21 g, 5.4 mmol). The reaction was let stir for 3 h, quenched with a minimal amount of H2O and concentrated. The residue was dissolved in EtOH and filtered through Celite©. The solvent was concentrated to give the title product (1.50 g, 83%). MS (ESI): mass calculated for C12H15N3, 201.1. m/z found 202.2 [M+H]+.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[OH:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[OH:31][C:32]1[CH:37]=[CH:36][C:35]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1ccc(O)cc1
Yield: 44 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 4-hydroxyphenylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as an off-white solid (44% yield); 1H-NMR (d6-DMSO) 1.37 (9H, s), 3.65 (2H, t), 4.05 (2H, t), 6.20 (1H, s), 6.68 (2H, d), 7.00 (2H, d), 9.25 (1H, s); 13C-NMR (CDCl3) 27.7, 41.7, 66.8, 114.7, 126.4, 131.4); MS ES(+) 222.1 (M+-tBu); Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.59; H, 7.05; N, 4.85. IR λmax=3402, 1672 cm−1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.[OH-].[Na+]>CS(C)=O.O>[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:2]3[C:7]([C:8]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=4)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CN1CCCN(c2ccc(CN)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN1CCCN(c2ccc(CNc3ncccc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 8.4 %

Procedure:
A mixture of 2-chloro-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide (1.00 g, 3.7 mmol) and 4-(4-methylhexahydro-1,4-diazepin-1-yl)benzylamine (0.63 g, 2.9 mmol), in 5 mL of DMSO, was heated in a sealed tube at 70–75° C. for 35 h. This reaction mixture was diluted with 250 mL of water, basified with 2 N NaOH, and extracted with ethyl acetate and evaporated to give 0.83 g crude product. Flash chromatography purification with 10% MeOH—CHCl3, 1% NH4OH gave the title product (0.11 g, 8.5%).
Reaction SMILES: N[C@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=O.[CH:13]1([NH:20][C:21]([NH2:23])=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([NH:20][C:21]2[S:22][C@@H:2]([CH2:6][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:3](=[O:5])[N:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)S[C@H]1CC1CCCCC1

Procedure:
Synthesis was performed from (2R)-2-amino-3-cyclohexylpropanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[OH:11])[C:7](=[O:12])[CH2:6][CH2:5]2.IC.[C:15](=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[OH:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:12])=[CH:3][C:2]=1[O:1][CH3:15]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCc2cc(O)c(O)cc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(cc1O)C(=O)CC2

Procedure:
A mixture of Example 63 (2.0 g, 12 mmol), iodomethane (1.9 mL, 30 mmol), and lithium carbonate (2.2 g, 30 mmol) in N,N-dimethylformamide (40 mL) was heated to 55° C. for 24 hours. The solution was concentrated under vacuum and was diluted with a 2% solution of hydrochloric acid in water. The precipitate was collected by filtration and was dried under high vacuum to provide the desired product. 1H NMR (500 MHz, CD3OD): δ 2.63 (t, J=6 Hz, 6H), 3.05 (t, J=6 Hz, 6H), 3.98 (s, 3H), 7.05 (s, 2H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23].Cl.O1CCOCC1>C(O)C>[CH2:1]([S:8][C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([Cl:19])[CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1cc(SCc2ccccc2)n2nccc2n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1cccc(Nc2cc(SCc3ccccc3)n3nccc3n2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To the reaction flask, 7-(benzylthio)-5-chloropyrazolo[1,5-a]pyrimidine (3.45 g, 12.5 mmol) was added along with 3-chloroaniline (3.3 mL, 31.3 mmol), 4N HCl in dioxane (3.1 mL, 12.5 mmol), and ethanol (42 mL). The reaction was stirred at reflux for 12 hours then cool to room temperature. Excess solvent was removed under vacuum and the residue was diluted with water. The mixture was made basic with 3N NaOH, filtered and washed with water. The product, 7-(benzylthio)-N-(3-chlorophenyl)pyrazolo[1,5-a]pyrimidin-5-amine, was collected as a solid in 90% yield after drying under vacuum overnight. LCMS (M+1=376)
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:29][C:30](=O)[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30](=[O:29])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH3:37])[N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: COC(=O)Cc1nc(C)no1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 34 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine and (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid methyl ester with heating for 2 days to afford the title compound as tan solid (65 mg, 34%). LC/MS (Method B) 4.05 min, [M+1]+ 491.
Reaction SMILES: Cl.[C:2]1([CH:8]([C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[C:16]([NH:9][CH:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]([CH3:15])([CH3:14])[C:11]([OH:13])=[O:12])([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)C(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
The obtained β-phenyl-α,α-dimethyl-β-alanine hydrochloride (2.0 g, 10.8 mmol) was dissolved in a 10% aqueous solution of sodium carbonate (46 ml). To the resulting solution, a solution of Fmoc-Cl (3.35 g, 12.96 mmol) in dioxane (20 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature overnight. The solvents were distilled off and the residue was dissolved in water and washed with ether. The aqueous layer was adjusted to pH 3 with concentrated HCl under cooling with ice and extracted with ethyl acetate. The collected ethyl acetate layer was washed with a saturated solution of NaCl and dried over anhydrous sodium sulfate. The solvent was distilled off and the obtained oil was applied to a silica gel column (2.5×40 cm) and eluted with a mixed solution (chloroform:methanol=50:1). The desired fractions were collected and the solvents were distilled off to yield a crystal of N-Fmoc-β-phenyl-α,α-dimethyl-β-alanine (1.21 g, 26.6%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH2:11])[CH2:9][CH3:10]>C(Cl)Cl>[CH2:8]([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:9][CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CCCN
Solvent: ClCCl
Product: CCCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 ml (50 mM) of ethyl bromoacetate were added dropwise to a solution of 20.5 ml (250 mM) of n-propylamine in 50 ml of CH2Cl2 at 0°. The reaction mixture was then warmed to room temperature and stirred for 1 hour, then concentrated to remove volatiles through a short path distillation head at atmospheric pressure. The residual liquid was taken up in ether and washed with saturated aqueous NaHCO3. The layers were separated and the ether layer was washed once with brine then dried over anhydrous MgSO4. The ether was removed to yield 7.16 g of ethyl N-(n-propyl)glycinate as a pale yellow liquid.