Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](OCC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][OH:15]
Reactant: CCOC(=O)c1cnoc1-c1cc(Cl)ccc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of ethyl 5-(2,5-dichlorophenyl)isoxazole-4-carboxylate (6.40 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.5 M toluene solution, 33 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 5-(2,5-dichlorophenyl)-4-isoxazolylmethanol (3.86, yield 71%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) and recrystallized from isopropyl ether-hexane to give a colorless prism. melting point: 51–52° C.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH2:16][CH2:15][O:14][C:12]3=2)[CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:23])([CH3:3])[CH3:2].O1CCOCC1.[Mn]([O-])(=O)(=O)=O.[K+].C=O>O>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[CH2:16][CH2:15][O:14][C:12]3=2)[C:7]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:6][C:5]1=[O:23])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NC(c2ccccc2)c2ccc3c(c21)OCC3
Agent: O=[Mn](=O)(=O)[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2ccc3c(c21)OCC3

Procedure:
To a stirred solution of 4.2 g. of 1-isopropyl-3,4,7,8-tetrahydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one in 180 ml. of dioxane cooled to 8°±5°C. is added dropwise a solution of 2.3 g. of potassium permanganate in 100 ml. of water. After the addition is completed 1.5 ml. of formalin solution is added. The solids which precipitate are removed by filtration and the filtrate concentrated in vacuo to obtain an oil of 1-isopropyl-7,8-dihydro-4-phenyl-furo[3,2-h]quinazolin-2(1H)-one.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24]>>[NH:21]1[C:17]([C:13]2[CH:12]=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH2:22])=[O:24])=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=[CH:15][CH:14]=2)=[N:18][N:19]=[N:20]1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: NC(=O)c1cccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)c1
Yield: 12.7 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 3-aminocarbonylphenylboronic acid (10 mg, 0.06 mmol) giving 2.7 mg (13%) of the title compound. MS (ESI+) calcd for C18H14N6O3S2 426.056880, found 426.057610.
Reaction SMILES: [K].[C:2]([C:4]1[C:5]([N:7]([CH3:12])[C:8](=[O:11])[C:9]=1O)=[O:6])#[N:3].O=P(Cl)(Cl)[Cl:15]>>[C:2]([C:4]1[C:5]([N:7]([CH3:12])[C:8](=[O:11])[C:9]=1[Cl:15])=[O:6])#[N:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)C(O)=C(C#N)C1=O
Agent: [K]
Product: CN1C(=O)C(Cl)=C(C#N)C1=O
Yield: 56 %

Procedure:
19 parts of the potassium salt of 2-cyano-3-hydroxy-N-methylmaleimide (prepared by a method similar to that for the salts described in J.Amer.Chem.Soc. 80 (1958), 3924) and 15.3 parts of phosphorus oxytrichloride in 100 parts by volume of heavy naphtha are heated at the boil for half an hour, the hot mixture is then filtered, the filtrate is allowed to cool, and the resulting precipitate is filtered off under suction, washed with gasoline and dried. 9.6 parts (56% of theory) of 2-cyano-3-chloro-N-methylmaleimide of melting point 141°-143° C. are obtained. IR (KBr): 2270, 1720, 1630 cm-1.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].CN(C)C>C(O)C>[CH2:11]([O:10][C:8]([C:7]1[C:2]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[N:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:6]=1)=[O:9])[CH3:12]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Agent: CN(C)C
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1NCC(=O)O
Temperature: 2.5 °C
Yield: 99.6 %

Procedure:
A mixture of ethyl 4-chloro-2-phenylpyrimidine-5-carboxylate (21 g), glycine (6.6 g), trimethylamine (17.8 g) and ethanol (200 ml) is refluxed for four hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in water. To the mixture is added dropwise conc. hydrochloric acid under stirring at 0-5° C. until the value of the mixture is adjusted to pH 4. The precipitates are collected by filtration, and washed with water to give crude N-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinyl)glycine (24 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]3[O:16][CH2:15]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)C.[ClH:33]>CO>[ClH:33].[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:17])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2cc(OCC3CO3)ccc12
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Cc1cc(=O)[nH]c2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc12
Yield: 63 %

Procedure:
2.4 Grams of 4-methyl-7-(2,3-epoxypropoxy)carbostyril and 1.8 g of 4-phenylpiperazine are mixed with 30 ml of ethanol and heated for 3 hours under refluxing conditions. After cooling the reaction mixture, crystals thus precipitated are collected by filtration and washed with ether. The crude crystals thus obtained are dissolved in 50 ml of methanol and 3 ml of concentrated hydrochloric acid. The mixture then is concentrated under reduced pressure to dryness. The residue thus obtained is recrystallized from ethanol-ether to obtain 2.7 g (yield: 63%) of 4-methyl-7-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]carbostyril monohydrochloride in the form of colorless crystals with a melting point of 190°-191° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]=2[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:16]1([C:12]2[CH:13]=[CH:14][CH:15]=[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:9]=2[CH2:10][NH2:11])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1c(Nc2ccccc2)cccc1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCc1c(Nc2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1b above, 2-phenylamino-6-phenylbenzonitrile, (0.13 g, 0.48 mmol) was dissolved in dry tetrahydrofuran (20 mL) and stirred under argon in a room temperature water bath. Lithium aluminum hydride (0.182 g, 4.8 mmol) was added rapidly. After 5 minutes at room temperature the reaction mixture was heated to 60° C. for 2 hours. The reaction mixture was cooled to room temperature and anhydrous sodium sulfate was added followed by the addition of a freshly prepared saturated solution of anhydrous sodium sulfate. The solvent was evaporated and the residue triturated with ethyl acetate, filtered and evaporated. Flash chromatography on silica gel eluted with 0-2% methanol in methylene chloride gave the title compound as a white amorphous solid. mp 115-116° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:34])[CH2:30][NH:31][CH2:32][CH3:33])=[C:23]([CH2:35][CH3:36])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2].C(#N)C>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][NH:9][C@H:17]1[CH2:16][S:15](=[O:18])(=[O:19])[CH2:14][C@@H:13]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:34])[CH2:30][NH:31][CH2:32][CH3:33])=[C:23]([CH2:35][CH3:36])[CH:22]=2)[C@@H:12]1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1CC
Solvent: CC#N
Solvent: O
Product: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc1CC

Procedure:
The title compound was prepared in analogous manner as described for example 1o from N-{4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-ethyl-6-fluoro-phenyl}-2-ethylamino-acetamide to yield after preparative HPLC (Sunfire C18 OBD 5 μm, 100×30, 5-50% ACN in water+0.1% TFA gradient, 25 min) the title compound as a light yellow amorphous solid: UPLC RtD=1.084 min; ESIMS [M+H]+=548; 1H NMR (600 MHz, DMSO-d6+TFA): δ 9.96 (s, 1H), 9.70 (s, 1H), 9.0 (s, 1H), 8.90 (s, 1H), 7.63 (s, 1H), 7.44 (m, 1H), 7.37 (m, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 4.26 (m, 2H), 4.02 (m, 2H), 3.84 (d, 1H), 3.66 (dd, 1H), 3.61 (dd, 1H), 3.1-3.3 (m (3H), 3.0 (m, 2H), 2.78 (d, 1H), 2.50 (m, 3H), 2.11 (m, 1H), 1.26 (s, 9H), 1.19 (t, 3H), 1.10 (t, 3H).
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:25]2[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CN(C)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (5.00 g, 22.7 mmol) in DCM (200 mL, 3 mol) was added dimethylpiperidin-4-yl amine (2.91 g, 22.7 mmol). DIPEA (11.9 mL, 68.1 mmol) and HOBt (5.21 g, 34 mmol) were added, followed by EDCI (5.22 g, 27.2 mmol). The mixture was stirred for 12 hours, then washed with water (300 mL), a saturated aqueous NaCl solution (300 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford 4.5 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([CH2:34][N:35]2[CH:39]=[C:38](C3OC(C)(C)C(C)(C)O3)[CH:37]=[N:36]2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].O>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]([CH2:34][N:35]2[CH:39]=[C:38]([C:2]3[CH:3]=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][C:8]([CH2:12][C:13]3[N:17]5[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]5=[N:15][N:14]=3)=[CH:7][CH:6]=4)[CH:37]=[N:36]2)[CH2:33]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CC(Cn2cc(C3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Cc1ccc2nnc(Cc3ccc4ncc(Br)cc4c3)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2nnc(Cc3ccc4ncc(-c5cnn(CC6CN(C(=O)OC(C)(C)C)C6)c5)cc4c3)n2n1
Yield: 27.4 %

Procedure:
To a microwave vessel was added 3-bromo-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (476 mg, 1.35 mmol, 1 equiv), 3-[4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-pyrazol-1-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.37 mmol, 2.5 equiv), K2CO3 (393 mg, 2.84 mmol, 2.0 equiv) followed by dioxane (12 mL) and water (6 mL). The solution was degassed with nitrogen for 10 min and then dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (44 mg, 0.06 mmol, 0.05 equiv) was added. The microwave vessel was capped and reacted in a microwave reactor at 130° C. for 30 min. The microwave vessel was cooled and then the mixture was extracted into dichloromethane and washed with water. The volatiles were removed in vacuo and the residue absorbed onto silica gel and purified by flash chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to obtain 3-{4-[6-(6-Methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinolin-3-yl]-pyrazol-1-ylmethyl}-azetidine-1-carboxylic acid tert-butyl ester (189 mg, 28% yield). Analytical data presented in Table 2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[N:21][C:20]=2[CH:22]=1
Reactant: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CN
Reactant: Clc1ccc2oc(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Temperature: 40 °C

Procedure:
A mixture of (2S,3R)-allyl 2-(aminomethyl)-3-methylpiperidine-1-carboxylate (0.804 g, 3.787 mmol), 2,5-dichlorobenzo[d]oxazole (0.712 g, 3.787 mmol) and DIPEA (1 mL, 5.68 mmol) in acetonitrile (15 mL) was heated at 40° C. overnight. The solvent was removed in vacuo and the crude was purified via silica gel with 0˜100% EtOAc/hexanes to obtain the title compound. ESI-MS (m/z): 364 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11](O)=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(N)([NH2:20])(=O)=O.N1C=CC=CC=1>O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]([NH2:20])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Reactant: NS(N)(=O)=O
Solvent: c1ccncc1
Solvent: O
Product: Cc1c([N+](=O)[O-])cc(C(N)=O)c2nc[nH]c12
Temperature: 25 °C
Yield: 85.3 %

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) (0.692 g, 3.12 mmol), sulfamide (0.600 g, 6.26 mmol), and pyridine (8 mL) is heated at reflux for about 16 hours. The resulting heterogeneous reaction mixture is cooled to ambient temperature, diluted with water (10 mL) and cooled to 0° C. for 1 hour. The solids that form are filtered, washed with water (10 mL) and methanol (10 mL), and dried to obtain 7-Methyl-6-nitro-1H-benzimidazole-4-carboxamide (25) as a cream colored solid (0.586 g, 85% yield).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][CH2:5][C:6](O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([CH:20]([NH2:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32]>C1(C)C=CC=CC=1.CCOCC.O>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]\[C:31]([OH:33])=[O:32].[CH3:3][O:4][CH2:5][CH2:6][NH:25][CH:20]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([Cl:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19]1)[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: COCC(=O)O
Reactant: CC(C)CC(N)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCCNC(CC(C)C)C1(c2ccc(Cl)cc2)CCC1
Reaction time: 16 h

Procedure:
Sodium borohydride (2.5 g) was added portionwise to a stirred solution of methoxyacetic acid (26.4 g) in toluene (300 ml) under an atmosphere of nitrogen and stirring was continued for 16 hours. A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine (5 g) in toluene (50 ml) was then added and the mixture was heated under reflux with stirring for 24 hours. After cooling the reaction mixture, water (200 ml) was added and the mixture was basified with 16N aqueous sodium hydroxide solution. The product was extracted into ether and the extracts were washed with water, dried and evaporated to give a brown oil which was dissolved in ether (30 ml). A solution of maleic acid (4.8 g) in ether (250 ml) was added. The solid which precipitated was collected, dried and recrystallised from ethyl acetate with hot filtering to give N-(2-methoxyethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine maleate (m.p. 131°-133° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH:22]4[CH2:25][CH:24]([C:26]([OH:28])=O)[CH2:23]4)[CH:19]=3)[N:14]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[N:39]1([C:26]([CH:24]2[CH2:23][CH:22]([CH2:21][C:18]3[CH:19]=[C:20]4[C:10]5([CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]5)[CH2:13][N:14]([C:29]([O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])=[O:30])[C:15]4=[CH:16][CH:17]=3)[CH2:25]2)=[O:28])[CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)O)C3)cc12
Reactant: C1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(CC3CC(C(=O)N4CCC4)C3)cc12
Reaction time: 15 h
Yield: 59.6 %

Procedure:
3-((1′-(tert-Butoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)carbonyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)methyl)cyclobutanecarboxylic acid (17.5 mg, 0.033 mmol) was dissolved in methylene chloride (1 mL) Thereafter, azetidine hydrochloride (6.0 mg, 0.064 mmol), triethylamine (9.0 μL, 0.065 mmol), and PyBOP (34.0 mg, 0.065 mmol) were added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 15 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain 1-(2-(trimethylsilyl)ethyl) 1′-tert-butyl 5-((3-(azetidine-1-carbonyl)cyclobutyl)methyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (11.2 mg, 60%) in the form of a light brown oily product.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:15])[CH3:14])[C:9]2=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:19][S:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Br:16])=[N:7][N:8]([CH:13]([CH3:14])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)n1nc(Br)c2ccc(S)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a solution of 7-mercap-to-2-isopropyl-4-bromo-2H-phthalazin-1-one (0.77 g, 2.6 mmol) in THF (8 ml), was added NaH (60%, 0.13 g, 3.1 mmol) portion-wise. After stirring for 5 min, methyl iodide (0.44 g, 3.1 mmol) was added dropwise and stirring was continued for four hours. The mixture was concentrated under vacuum and the residue was subjected to flash column chromatography (elution: 90% heptane, 10% EtOAc) to give the title compound (0.44 g, 54% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 8.02 (1H, d), 7.88 (1H, d), 7.75 (1 H, d), 5.26-5.15 (1H, m), 2.59 (3H, s), 1.35 (6H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:13]3[C:14](=[O:19])[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C1CCC=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCCC[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Yield: 95.2 %

Procedure:
Platinum oxide (10 mg) was added to a solution of (4R*,10aS*)-4-(4-fluorophenyl)-1,3,4,7,8,10a-hexahydro-2H-pyrido[1,2-a]azepin-6-one (146 mg) in methanol (5 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for 25 hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain 140 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: O.[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([C:18]#N)[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3].CC(O)=[O:22]>[Ni].N1C=CC=CC=1>[CH2:2]([O:4][C:5]([C:7]1[C:16]([Cl:17])=[CH:15][C:14]2[C:9](=[C:10]([CH:18]=[O:22])[CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(C#N)cccc2cc1Cl
Reactant: CC(=O)O
Agent: [Ni]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2c(C=O)cccc2cc1Cl
Temperature: 125 °C

Procedure:
NaH2PO2×H2O (2.12 g, 20.02 mmol, 8.0 equiv) and Raney nickel (1.50 g) were added at room temperature to a solution of 3-chloro-8-cyano-naphthalene-2-carboxylic acid ethyl ester (0.65 g, 2.50 mmol) in pyridine (16 ml)/AcOH (8 ml)/H2O (8 ml). The heterogeneous mixture was heated to 125° C. for 2 hours. After cooling and filtering off the Raney nickel catalyst, the reaction mixture was diluted with water (100 ml). After extraction with EtOAc (2×400 ml), the combined organic layers were washed with brine (2×50 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of hexane/EtOAc 100:0 to 90:10) to afford the title compound (350 mg, 53%, inseparable 1:1.5 mixture of regioisomers A:B) as a white solid. 1H NMR (400 MHz, CDCl3): δ=10.35 (s, 1H isomer B), 10.33 (s, 1H isomer A), 9.70 (s, 1H isomer B), 9.41 (s, 1H isomer A), 8.39 (s, 1H isomer A), 8.14 (d, J=8.4 Hz, 1H isomer A). 8.08 (dd, J=7.1/1.2 Hz, 1H isomer B), 8.04-8.01 (m, 1H isomer A+1H isomer B), 7.99 (1H isomer B), 7.77-7.70 (m, 1H isomer A+1H isomer B), 4.48 (q, J=7.1 Hz, 2H isomer B), 4.47 (q, J=7.1 Hz, 2H isomer A), 1.46 (t, J=7.1 Hz, 3H isomer B), 1.45 (t, J=7.1 Hz, 3H isomer A). MS (ES+): 263 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:15][C:16](Cl)([CH3:19])[C:17]#[CH:18]>CC#N>[CH3:15][C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:19])[C:17]#[CH:18]
Reactant: C#CC(C)(C)Cl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)(C)Oc1ccc(I)cc1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a solution of 4-iodophenol (5.01 g, 22.8 mmol) in CH3CN (100 mL) containing K2CO3 (15.7 g, 0.114 mol) was added KI (4.91 g, 29.6 mmol) followed by 3-methyl-3-chlorobutyne (7.01 g, 68.3 mmol) at room temperature. The reaction was heated to 80° C. for 60 hours. The reaction was cooled to room temperature, quenched with 2.5N NaOH and extracted with ether. The combined organic extracts were washed with 2.5N NaOH (2X eq. vol.), dried over anhydrous K2CO3 and concentrated. The residue was taken up in a minimal amount of 10% ether/petroleum ether and filtered through a 2" silica gel pad, using 10% ether/petroleum ether elution. The filtrate was concentrated to give 6.04 g, (93%) of product.