Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:18]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)[CH3:19]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN1CC(=O)Nc2cc([N+](=O)[O-])c(OC)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (400 mg, 1.69 mmol) in methanol (100 mL) was added acetaldehyde (2.0 mL, 30 mmol) followed by acetic acid (0.29 mL, 5.0 mmol). The mixture was stirred for 20 minutes at room temperature whereupon sodium triacetoxyborohydride (1.10 g, 5.0 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated on a rotary evaporator. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography over silica gel (0-5% MeOH-EtOAc) gave 4-ethyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (330 mg, 72%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 7.60 (s, 1H), 7.35 (s, 1H), 3.91 (s, 3H), 3.86 (s, 2H), 3.35 (s, 2H), 2.55 (q, J=6 Hz, 2H), 1.06 (t, J=6 Hz, 3H); MS (m/e) 266 (M+1); mp 168° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH3:44])[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][O:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:41](=[O:42])[C:38]1[CH:39]=[CH:40][C:35]([CH3:44])=[CH:36][CH:37]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1noc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3onc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
A solution of {3-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester (method 47) (100 mg, 0.213 mmol) in DCM (4 ml) was added p-toluoyl chloride (66 mg, 0.426 mmol) followed by triethylamine (65 mg, 0.639 mmol). The mixture was stirred at 30-40° C. for 2 days. The mixture was then diluted with DCM, washed with saturated sodium bicarbonate aq. The organic phase was dried, filtered, and concentrated. The crude oil was purified by ISCO (solvent: EtOAc-hexane) to give {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6 -yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester as white solid (115 mg, 0.196 mmol). m/z: 588 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: CN1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 1-methylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 17.6 mg of 261. MS (Q1) 561.8 (M)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:28]=[CH:27][C:22]([C:23](OC)=[O:24])=[CH:21][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(/C=C/c2nc(-c3ccc4ccccc4c3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc3ccccc3c2)nc1/C=C/c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
Methyl (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzoate (9.30 g) was suspended in THF (250 ml), and lithium aluminum hydride (955 mg) was added little by little at 0° C. After mixture stirring at room temperature for 1 hour, water (5 ml) was added; the insoluble substances were filtered off. The filtrate was concentrated under reduced pressure; the resulting crystal was recrystallized from dichloromethane-methanol to yield (E)-4-[2-[5-methyl-2-(2-naphthyl)-4-oxazolyl]vinyl]benzyl alcohol (8.00 g, 93%) as colorless prisms having a melting point of 173°-174° C.
Reaction SMILES: [BH4-].[Li+].C(O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:10]([F:21])[CH:9]=1)(=O)C.[O:22]1CCC[CH2:23]1>>[F:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:23][OH:22])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: C1CCOC1
Reactant: COCCOCOc1ccc(COC(C)=O)cc1F
Agent: [BH4-]
Agent: [Li+]
Product: COCCOCOc1ccc(CCO)cc1F
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
2.4 g (107 mmol) of lithium borohydride is added in portions to a solution of 9.7 g (36 mmol) of [3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate in 100 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 1.5 h and then it is poured into 500 ml of ice and extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. 8.6 g (99%) of 2-[3-fluoro-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol is obtained in the form of a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.CC1N=CN=[C:38]([C:42](O)=[O:43])C=1>>[CH2:42]([O:43][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH3:1])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:38]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: Cc1cc(C(=O)O)ncn1
Product: CCOc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)n1

Procedure:
rac-N-(3-{4-[5-(2-Ethoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-ethoxy)-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.92 min; [M+H]+=458.20.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.[H-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[O:19])=[CH:15][CH:16]=2)[N:4]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:3]=1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)n[nH]c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)nn(CCN3CCOCC3)c2n1
Yield: 9.7 %

Procedure:
In analogy to GP 5, reaction of 1-[4-(3-Amino-6-isopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (136 mg, 0.3 mmol, 1 eq.) with 39.3 mg NaH, 167 mg 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.9 mmol, 3 eq.), 0.12 mL triethylamine (0.9 mmol, 3 eq.) in 3+3 mL DMF yielded after HPLC purification 16.6 mg of the desired product (10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:22]([C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:30])([F:29])[F:31])[C:9]=4[CH:17]=3)=[CH:26][CH:25]=2)=[O:24])[CH2:41][CH2:40]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2ccccc2Cl)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-chlorophenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=625.96 (M+H+); retention time=1.07 minutes.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:40]2[CH:41]=[CH:42][C:37]([CH2:36][Cl:35])=[CH:38][CH:39]=2)=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (52 mg, yield 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:11]([O-:25])[C:12]([O:23][CH3:24])=[C:13]([CH2:15][O:16]C2CCCCO2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>Cl.C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:26][CH:27]([CH3:29])[CH3:28])=[N+:11]([O-:25])[C:12]([O:23][CH3:24])=[C:13]([CH2:15][OH:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(COC2CCCCO2)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1c(CO)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
There was stirred, for 30 minutes at room temperature, a mixture of 80 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide, 1 ml of methanol and one drop of concentrated hydrochloric acid. The reaction mixture was mixed with diethyl ether, then the mixture was washed with an aqueous solution saturated over sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel thin layer chromatography (developing solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization from diethyl ether-n-hexane to obtain 63 mg of 3-benzyloxy-5-hydroxymethyl-2-isobutyl-6-methoxypyrazine 1-oxide (Compound B-16) as colorless needle-like crystals having a melting point of 68.0°-69.2° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH:20]C(OCC2C=CC=CC=2)=O)[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].C1CC=CCC=1>CO.[Pd]>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]([NH2:20])[CH3:19])[CH:12]=1)([CH3:10])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: CC(N)Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1

Procedure:
To a mixture of {1-[3-(2-benzyloxycarbonylamino-propyl)-phenyl]-1-methyl-ethyl}-carbamic acid tert-butyl ester (0.28 g, 0.65 mmol), 1,4-cyclohexadiene (0.31 mL, 3.25 mmol) and Pd/C (cat.) in methanol was heated to reflux for 17 h. The mixture was filtered through celite and concentrated to afford light yellow oil. M+1=293.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][CH:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][CH:19]([NH:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(N=C=O)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(NC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1)c1ccccc1
Yield: 97.3 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 12.51 mg (0.0852 mMol) α-methylbenzyl isocyanate, 24.0 mg (97%) of the title compound were recovered.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>CCOC(C)=O.CCCCCCC>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.477 g of tertbutyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.268 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The We compound is obtained as a slightly yellowish oil. Rf=0.11 (1:1 EtOAc-heptane); Rt=5.89.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][NH:39][CH:40]=O)[CH2:33][CH2:32]2)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][N:39]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[C:8]([S:11][CH3:12])[CH:7]=4)[N:1]=[CH:40]3)[CH2:33][CH2:32]2)=[CH:16][CH:15]=1
Reactant: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CSc1ccc(N)c(C(=O)O)c1
Product: CSc1ccc2ncn(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Reaction time: 5 h
Yield: 41.5 %

Procedure:
A mixture of 3.7 parts of 2-amino-5-(methylthio)benzoic acid and 8.9 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide was stirred for 5 hours at 150°-160° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and acetonitrile. The product was filtered off and dried, yielding 4.5 parts (41.5%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-4(3H)-quinazolinone; mp. 101.4° C. (compound 138).
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>CCCCCCC.CCOC(C)=O>[I:43][CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17]
Reactant: II
Reactant: COc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Yield: 81.7 %

Procedure:
The compound (S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF34) (2.70 g, 12.0 mmol), triphenylphosphine (6.92 g, 26.4 mmol), Imidazole (1.96 g, 28.8 mmol) and I2 (8.53 g, 33.6 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (II 1MF36) (3.54 g, 82%). 1H NMR (CDCl3) δ 6.92 (d, J=8.4 Hz, 1H), 6.63 (d, J=2.8 Hz, 1H), 6.53 (dd, J=2.8 Hz, J=8.8 Hz, 1H),4.54 (q, J=14.8 Hz, J=23.6 Hz, 2H), 3.92 (d, J=7.4 Hz, 2 H), 3.80 (s, 3H), 3.18 (dd, J=1.0 Hz, J=6 Hz, 2H), 2.17-2.08 (m, 1H), 1.05 (d, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 165.4, 155.6, 139.6, 129.4, 117.7, 108.0, 102.5, 68.0, 56.1, 46.1, 33.6, 18.9, 12.0.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:10]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Salicylaldehyde (50 mmoles) was dissolved in dry dimethylformamide (DMF) (100 ml) at room temperature. Benzyl bromide (75 mmoles) was then added followed by the potassium carbonate (125 mmoles) and the mixture stirred at room temperature for 48 h. The mixture is then filtered to remove the potassium carbonate and the filtrate is mixed with ethyl acetate. The organic phase is washed with water (3×200 ml), brine and dried over MgSO4. The solution is then filtered and evaporated in vacuo to provide the crude material. Solid products are washed with ethyl ether to provide the clean desired product or in the case of aldehydes which are oils, they are purified by silica gel chromatography.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=1.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1.FC1C=C(C=C(S(C)(=O)=O)C=1)OCCNCCC>C(O)C>[CH:18]1([CH2:17][NH:16][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([F:15])[CH:6]=2)[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: CS(=O)(=O)c1cc(F)cc(OCCBr)c1
Agent: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Solvent: CCO
Product: CS(=O)(=O)c1cc(F)cc(OCCNCC2CC2)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-fluoro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol) and aminomethylcyclopropane (0.11 ml, 1.3 mmol) in ethanol (5 ml). MS m/z (relative intensity, 70 eV) 287 (M+, 2), 246 (6), 138 (2), 84 (bp), 56 (14).
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.C[CH2:26][N:27](C(C)C)C(C)C.C(Br)#N>C(Cl)Cl.C1COCC1>[C:26]([N:22]1[CH2:23][CH2:24][CH:19]([N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:20][CH2:21]1)#[N:27]
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(C#N)CC2)cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (310 mg, Intermediate 20) and DIPEA (0.42 mL) in CH2Cl2 (10 mL) and THF (10 mL) is added bromocyane (120 mg) and the mixture is stirred at room temperature for 12 h. The mixture is concentrated, ethyl acetate and water are added, the organic layer is dried (MgSO4) and concentrated to yield the title compound. LC (method 3): tR=1.07 min; Mass spectrum (ESI+): m/z=352 [M+H]+.
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)CC[C@](C)(C(=O)O)c1ccccc1
Yield: 73 %

Procedure:
To a solution of Example 40A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.02 g, 73%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([O:16][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:15]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COCC(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)COC(=O)COC

Procedure:
71 ml of ethyl 4-chloro-3-oxo-butyrate are reacted with 89.5 g of methoxyacetic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. The product is purified by bulb tube distillation.