Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[CH2:6][NH:7][CH:8]1[C:17]2[N:12]([C:13](=[O:30])[C:14]3[CH:27]=[C:26]([CH3:28])[C:25]([CH3:29])=[CH:24][C:15]=3[C:16]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10][CH2:9]1.[CH2:35]=O.[BH4-].[Na+]>>[CH3:28][C:26]1[C:25]([CH3:29])=[CH:24][C:15]2[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:17]3[N:12]([C:13](=[O:30])[C:14]=2[CH:27]=1)[CH2:11][CH2:10][CH2:9][CH:8]3[N:7]([CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:33]=[C:32]([CH3:34])[CH:31]=1)[CH3:35]
Reactant: Cc1cc(C)cc(CNC2CCCn3c2c(-c2ccccc2)c2cc(C)c(C)cc2c3=O)c1
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cc(C)cc(CN(C)C2CCCn3c2c(-c2ccccc2)c2cc(C)c(C)cc2c3=O)c1

Procedure:
The compound obtained in Example 233 and formalin were reacted and treated with sodium borohydride in the same manner as in Example 233 to yield the title compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(OCc3ccccc3)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 30, (100 mg, 0.20 mmol), tetrahydrofuran (3 mL), and methanol (1 mL) was treated with 2.5 N sodium hydroxide (1 mL) at room temperature. After 18 hours the mixture was concentrated to one-third of its original volume, diluted with water (3 mL) and treated with 2 N hydrogen chloride (2 mL). The mixture was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow/orange solid, 90 mg, 0.18 mmol, 93% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.51 (m, 7H), 1.57-1.69 (m, 1H), 1.74-1.89 (m, 1H), 1.95-2.07 (m, 1H), 2.18-2.29 (m, 1H), 2.82-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.57 (ddd, J=13.70, 9.40, 4.30 Hz, 1H), 4.91 (dd, J=9.53, 5.50 Hz, 1H), 5.31 (q, J=12.35 Hz, 2H), 6.84 (d, J=8.86 Hz, 1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H), 7.40-7.53 (m, 5H), 7.81-7.88 (m, 2H), 8.09 (d, J=8.06 Hz, 1H), 13.03 (s, 1H). ES-MS m/z 492 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]I>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:29])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Reactant: CI
Product: CCc1cc(OC)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Yield: 75 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl -6-methoxy benzene was prepared in 75% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and methyliodide.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15]1
Reactant: Clc1nc2ccccc2o1
Reactant: OCCN1CCNCC1
Solvent: CN(C)C=O
Product: OCCN1CCN(c2nc3ccccc3o2)CC1
Reaction time: 1 h

Procedure:
A 300 mg portion of 2-chlorobenzoxazole was dissolved in 2 ml of DMF. Under cooling with ice, 279 mg of 1-(2 -hydroxyethyl)piperazine was added to the thus prepared solution, and the reaction was carried out for 1 hour at the same temperature and then for 24 hours at room temperature. The reaction solution was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate and washed with sodium hydrogencarbonate aqueous solution (pH 8) and then with water. The resulting organic layer was dehydrated with sodium sulfate and concentrated under a reduced pressure to obtain 140 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28](=[O:37])[NH:29][C:30](=[NH:36])[N:31]2[CH:35]=[CH:34][CH:33]=N2)=[C:10]([C:13]2[CH:26]=[CH:25][C:16]([C:17]([NH:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[O:18])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:42].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([NH:29][C:30]([NH:31][CH2:35][CH2:34][CH2:33][OH:42])=[NH:36])=[O:37])=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[O:18])=[CH:25][CH:26]=2)[S:11][CH:12]=1
Reactant: NCCCO
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a solution of 4-(4-(2-chloro-phenyl)-3-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-thiophen-2-yl)-N-(1-ethyl-propyl)-benzamide (0.87 g, 0.16 mmol) in CH2Cl2 (2 mL) was added 3-aminopropanol (0.037 g, 0.040 mL, 0.50 mmol) and diisopropyl ethylamine (0.064 g, 0.087 mL, 0.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 4-[4-(2-chlorophenyl)-3-(2-{[[(3-hydroxypropyl)amino](imino)methyl]amino}-2-oxoethyl)thien-2-yl]-N-(1-ethylpropyl)benzamide (0.047 g) as a white solid. mp 109-110° C. MS (ES) m/z 541.12 ([M+H]+); Anal. Calcd for C28H33ClN4O3S.0.60 H2O: C, 60.93; H, 6.25; N, 10.15. Found: C, 60.57; H, 6.07; N, 10.02.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:12]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: Cc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(C)cc2C1=O
Yield: 83 %

Procedure:
A solution of 14.2 g of 6-methyl-1-indanone, 20.1 ml of 3-buten-2-ol and 140 mg of p-toluenesulfonic acid in 140 ml of 2,2-dimethoxypropane was boiled under reflux for 69 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 16.3 g (83%) of (RS)-2-(2-buten-1-yl)-6-methyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O.[NH2:25][NH2:26]>CCO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([NH:25][NH2:26])=[O:19])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: NN
Reactant: COC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(NC(=O)CCc2ccc(O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52 %

Procedure:
To a suspension of methyl 4-{[3-(3,4-dihydroxyphenyl)propanoyl]amino}benzoate (227 mg, 0.72 mmol) in EtOH (3.5 mL) was added hydrazine hydrate (0.55 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 117 mg of the title compound (52%) as a white solid in 99.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Br)=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2].[CH3:14][O-:15].[Na+]>CO.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([O:15][CH3:14])=[CH:9][CH:8]=[N:7][C:6]=1[Cl:12])[CH3:2]
Reactant: CCOC(=O)c1c(Br)ccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1c(OC)ccnc1Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 4-bromo-2-chloronicotinic acid ethyl ester (5.06 mmol) in 15 mL MeOH was added 1.0 mL of a solution of NaOMe (30% in MeOH). The reaction mixture was stirred at 40° C. for 4 h, cooled to RT, diluted with EtOAc and then quenched with sat. aq. NH4Cl solution. The organic layers was dried over MgSO4 and concentrated in vacuo to give the desired compound as brown oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=O)[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O1CCOCC1.Cl>[Zn].O>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(CCC(=O)CCc2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CCCCCc2ccc(OC)cc2)cc1
Yield: 111 %

Procedure:
A mixture of 1,5-bis(4-methoxyphenyl)pentan-3-one of Example 7 (57 g, 0.19 mole), amalgamated zinc (200 g), dioxane (250 ml), concentrated hydrochloric acid (250 ml) and 150 ml of water was refluxed overnight. A further 50 ml of concentrated hydrochloric acid was added after the first 6 hours. The organic layer was separated, diluted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 60 g of a thick oil. NMR and mass spectra confirmed the structure.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1>>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1nc2ccccc2o1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2nc3ccccc3o2)c1
Yield: 51.1 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (207 mg, yield: 51.1%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][S:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/C(CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCC(CSc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
A mixture of Example 384A (650 mg, 1.92 mmol) and 10% Pd/C (2.3 g, 2.2 mmol) in ethyl acetate (15 mL0 and methanol (5 mL) was stirred at room temperature under a hydrogen balloon for 6 hours and filtered through diatomaceous earth (Celite®). The pad was rinsed with hot ethyl acetate, and the combined organic phases were concentrated to provide the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C:11]3[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=3[C@@H:13]3[C@H:18]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16][CH2:15][N:14]3[C:8]=2[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[C:31]([N+:1]([O-:4])=[O:2])=[CH:30][C:9]2[O:10][C:11]3[CH:29]=[CH:28][CH:27]=[CH:26][C:12]=3[C@@H:13]3[C@H:18]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:17][CH2:16][CH2:15][N:14]3[C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCN2c3cc(Cl)c([N+](=O)[O-])cc3Oc3ccccc3[C@H]12)C(F)(F)F
Yield: 93.5 %

Procedure:
Nitric acid (50 μL, 1.10 mmol) was added at 0° C. to a suspension of trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (210 mg, 0.53 mmol) in 4 mL of CH2Cl2. After stirring the mixture was extracted with ethyl acetate and the organic layer was washed with 5% aq. sodium bicarbonate, dried (Na2SO4) and evaporated to give trans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (219 mg, 90%). Data: 1H-NMR (400 MHz, DMSO) 1.64-1.94 (m, 3H), 2.05 (br, 1H), 3.26 (t, J=8.0, 1H), 4.20 (d, J=8.0, 1H), 4.35 (d, J=8.0, 1H), 4.60 (dq, J=8.0, 3.0, 1H) 7.15 (m, 1H), 7.11-9.21 (6 ArH). (m/z)=443 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([CH:13]([OH:21])[CH2:14][O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=[CH:8]2.[CH3:22][S:23]([Cl:26])(=[O:25])=[O:24]>C(N(CC)CC)C>[ClH:26].[CH3:20][N:18]([CH2:17][CH2:16][O:15][CH2:14][CH:13]([C:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[CH:8]=[CH:9][CH:10]=1)[OH:21])[CH3:19]
Reactant: CN(C)CCOCC(O)c1cccc2cccc(N)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)CCOCC(O)c1cccc2cccc(NS(C)(=O)=O)c12

Procedure:
Triethylamine was added to 1-(8-amino-1-naphthyl)-2-[2-(N,N-dimethylamino)ethoxy]ethanol hydrochloride. The resulting mixture was reacted with methanesulfonyl chloride to obtain oily 2-[2-(N,N-dimethylamino)ethoxy]-1-(8-methylsulfonylamino-1-naphthyl)ethanol hydrochloride (compound No. 291).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH2:21]([NH:24][CH2:25][CH:26]=[CH2:27])[CH:22]=[CH2:23]>O1CCCC1>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])([O:15][N:24]([CH2:25][CH:26]=[CH2:27])[CH2:21][CH:22]=[CH2:23])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: C=CCNCC=C
Solvent: C1CCOC1
Product: C=CCN(CC=C)OP(=O)(CN(CC(=O)OCC)C(=O)C(F)(F)F)ON(CC=C)CC=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (3.3 g, 0.01 mole) in 25 ml. of tetrahydrofuran was added diallylamine (4.07 g, 0.042 mole) in 50 ml. of tetrahydrofuran. The mixture was stirred at room temperature overnight and was then filtered and the filtrate concentrated in vacuo. The residue was dissolved in ether, washed with water, 10% HCl, water, dried over MgSO4, and concentrated in vacuo. The residue was extracted with petroleum ether, and by concentrating the petroleum ether soluble material, ethyl N-trifluoroacetyl-N-(bis(diallylamino)phosphonomethyl)glycinate was obtained as a light yellow oil, ND =1.4536.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH:17]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:28][CH2:27]1
Reactant: O=CCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCN3CCN(c4ccccc4F)CC3)C2)c1
Yield: 45.4 %

Procedure:
3-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]propanal (30.3 mg, 0.122 mmol), 1-(2-fluorophenyl)piperazine (20.0 mg, 0.111 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (70.5 mg, 0.333 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 20.8 mg (50.3%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].Br[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Zn].C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Zn]
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)C(=O)c1ccc(Cl)c(Cl)c1
Yield: 63 %

Procedure:
A mixture comprising 10.0 g of 3,4-dichlorobenzoyl chloride, 9.31 g of ethyl 2-bromoisobutyrate and 90 ml of anhydrous diethyl ether, was dropwise added to 3.12 g of zinc in a nitrogen atmosphere, followed by a reaction for 15 hours under reflux. The reaction mixture was filtered through celite, and the filtrate was washed with 20% sulfuric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/19) to obtain 8.7 g of oily ethyl 2-(3′,4′-dichlorobenzoyl)isobutyrate. The NMR spectrum data of this product is as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:22][CH2:21][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27](B5OC(C)(C)C(C)(C)O5)[CH:28]=4)[O:23]3)[CH2:19][CH2:18]2)=[O:16])[CH:4]=1.Br[C:43]1[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=1)[C:48]([NH2:50])=[O:49].O1CCOCC1>C(Cl)(Cl)Cl.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>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:15]([N:17]2[CH2:18][CH2:19][C:20]3([CH2:31][C:30](=[O:32])[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:43]5[CH:44]=[N:45][CH:46]=[C:47]([CH:51]=5)[C:48]([NH2:50])=[O:49])[CH:28]=4)[O:23]3)[CH2:21][CH2:22]2)=[O:16])[CH:4]=1
Reactant: NC(=O)c1cncc(Br)c1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(B4OC(C)(C)C(C)(C)O4)ccc2O3)nc2c(OC)cccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(N)=O)c4)ccc2O3)nc2c(OC)cccc12
Reaction time: 21 h

Procedure:
350 mg of 1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[chroman-2,4′-piperidin]-4-one, 151 mg of 5-bromonicotinamide, 72.5 mg of Pd(PPh3)4 and 1.4 mL of 2M Na2CO3aq were heated with 1,4-dioxane at 100° C. and stirred for 21 hours. The reaction solution was diluted with CHCl3, filtered through Celite, and the filtrate was dried with magnesium sulfate and concentrated. The residue was purified through silica gel thin-layer chromatography (CHCl3/MeOH=9/1) to obtain the intended compound. 1H-NMR (400 MHz, CDCl3) δ: 8.90-9.00 (2H, m), 8.36 (1H, s), 8.15 (1H, s), 7.70-7.80 (2H, m), 7.40-7.55 (1H, m), 7.19 (1H, s), 7.17 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=7.8 Hz), 6.3-6.5 (1H, br), 5.7-6.1 (1H, br), 4.50-4.60 (1H, m), 4.10-4.15 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.55-3.70 (1H, m), 3.35-3.50 (1H, m), 2.88 (1H, d, J=16.6 Hz), 2.82 (1H, d, J=16.6 Hz), 2.20-2.30 (1H, m), 2.05-2.15 (1H, m), 1.80-2.05 (2H, m). MS [M+H]+=553.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]1=[O:24])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][C:13]2=[O:24])[C:3]([OH:25])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 8.6 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (0.205 g, 0.006 mol) in tetrahydrofuran-water (3:1, 5 mL) was added lithium hydroxide (504 mg, 0.012 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-(2-oxo-4-phenoxy-2,5-dihydro-pyrrol-1-yl)-propionic acid (170 mg, 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH2:40]C)[C:31]=3[CH:42]=2)=[CH:5][CH:4]=1.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>>[N:43]1([CH2:2][C:3]2[CH:4]=[CH:5][C:6]([CH:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:11][CH:10]3[O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]4[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=4[CH:42]=3)=[CH:7][CH:8]=2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: CCOCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Reactant: c1c[nH]cn1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(Cn4ccnc4)cc3)cc21

Procedure:
Analogously to Example 269a, 0.103 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-ethoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.013 g of imidazole are reacted. The title compound is obtained as a yellowish oil. Rf=0.47 (200:10:1 dichloromethane-methanol-25% conc. ammonia). Rt=4.34.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH3:9])[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]([Cl:13])[CH3:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cncc(Br)c1
Solvent: ClCCl
Product: CC(Cl)c1cncc(Br)c1

Procedure:
To a solution of 1-(5-bromo-pyridine-3-yl)-ethanol (201 mg, 1 mmol) in DCM (10 mL) was added dropwise thionyl chloride (200 uL). The resulting reaction mixture was heated to reflux for 3 hours before the solvent was removed in vacuo to give a crude product as a white solid. It was used directly in the next step without further purification.