Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:11]([OH:13])=O)[CH2:7][C@H:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C@:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][C@H:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1=C[C@@H](O)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To an ice cooled solution of 28 (50 mg, 37 mmol) and (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert-butyl ester in DMF (5 mL), DIPEA (47 mmol) and HATU (47 mmol) were added. After two hours the solution was concentrated and purified using column chromatography (toluene/ethyl acetate 3:1). This gave the title compound as a slightly yellow oil (50 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3-S)3-dimethylamino-pyrrolidine-1 carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-Chloro-phenyl)3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (60.1 mg, 5%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])#[N:2].CO.[ClH:13].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(Cl)Cl>[ClH:13].[CH2:15]1[CH2:16][CH:14]1[CH2:17][NH:18][C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])=[NH:2]
Reactant: NCC1CC1
Reactant: N#CCCN1CCOC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: N=C(CCN1CCOC1=O)NCC1CC1
Temperature: -15 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A solution of N-(cyanoethyl)oxazolidinone 18 (30 g, 0.21 mol) in dry methanol (10.9 g, 0.34 mol) and dry CH2Cl2 (60 mL) was saturated with dry HCl at -15° to 0° C. The mixture was then stirred for 6 h at 0°-20° C. The mixture was evaporated and dried in vacuo for 1 h. The crystalline imidoester hydrochloride was dissolved in dry methanol (120 mL) and cooled to -15° C. To the stirred solution cyclopropylmethylamine (31.2 g, 0.44 mol) was added in drops over a period of 20 min while maintaining the temperature at -15 to 0° C. The mixture was then stirred at -10° C. for 45 min and evaporated. The residue was dissolved in methanol, treated with ether until turbid and was refrigerated for 6 days. The colorless crystalline material was collected and dried to give 59 (28.7 g, 55%), mp 86°-88° C. 1H NMR (DMSO--d6) δ 0.28 (m, 2, --CH--CH2), 0.55 (m, 2, --CH--CH2), 1.05 (m, 1, --CH), 2.68 [t, 2, --CH2 --C(N=)], 3.07 (d, 2, --NH--CH2), 3.54 [t, 2, --CH2 --CH2 --C(N=)], 3.67 (t, 2, --O--CH2 --CH2). 4.30 (t, 2, --OCH2).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][CH:33]([CH3:36])[CH2:32][CH2:31]4)=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>O.CCO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([O:27][CH2:28][CH2:29][N:30]4[CH2:31][CH2:32][CH:33]([CH3:36])[CH2:34][CH2:35]4)=[C:22]([CH:24]([OH:26])[CH3:25])[CH:23]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)c1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1CCN(CCOc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2C(C)O)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 30 mg (0.74 mmol) of sodium borohydride in 3 mL of water was added to a solution of 0.32 g (0.68 mmol) of 1-{5-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl}ethanone (Example 13.1) in 8 mL of EtOH and the mixture was stirred for 30 minutes at 50° C. The reaction mixture was evaporated down in vacuo, and the residue was stirred for 5 minutes with 4 mL of 1N aqueous HCl, diluted with EtOAc, and neutralized with saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. The residue was triturated with acetonitrile and a little EtOAc, the precipitate was filtered off, and dried in the air. Yield: 100 mg (31% of theoretical); C29H31ClN2O2 (M=475.021); calc.: molpeak (M+H)+: 475/477 (Cl); found: molpeak (M+H)+: 475/477 (Cl); HPLC-MS: 5.20 minutes (method A).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:10]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:11]1[CH:10]=[C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Product: Cc1noc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)c1Br
Yield: 22 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-biphenylsulfonamide was prepared in the same manner as described in Example 200b from 5-amino-4-bromo-3-methylisoxazole and 3-biphenylsulfonyl chloride in 22% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 78-82° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Nc1ncccc1F
Solvent: ClCCCl
Product: O=C(CCl)Nc1ncccc1F
Temperature: 80 °C

Procedure:
2-Amino-3-fluoropyridine (1.5 g) was dissolved in DCE (15 mL) and chloroacetylchloride (1.1 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled and the resulting solid was filtered off, washed with DCE, MeCN and pentane then suspended in dichloromethane and aqueous NaHCO3 (sat) was added. The organic phase was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the title compound as a white solid (800 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11](=O)[CH3:12])[CH:8]=[CH:9][CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][C:2]([F:15])([F:14])[F:1])[CH:6]=1)[CH3:12])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1cccc(OCC(F)(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(OCC(F)(F)F)c1
Yield: 72 %

Procedure:
The title compound is prepared in 72% yield (0.71 g, colorless oil) from 1-(3-(2,2,2-trifluoroethoxy)phenyl)ethanone (0.67 g, 3.08 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:35])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][OH:17])[NH:10]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][O:17][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:10]1
Reactant: CC1(CO)COC(=O)C(C)(C)N1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(COC(=O)C(C)(C)C)COC(=O)C(C)(C)N1
Reaction time: 16 h

Procedure:
A solution of 2.63 g (0.021 mol) of pivaloyl chloride is added dropwise to a solution of 3.5 g (0.02 mol) of 3,3,5-trimethyl-5-hydroxymethylmorpholin-2-one (prepared in accordance with J. T. Lai.: Synthesis 122 (1984)) and 0.1 g of 4-dimethylaminopyridine in 20 ml of dichloromethane at 15° C. After stirring for 16 hours, another 0.75 ml of pivaloyl chloride is added and the reaction mixture is stirred for 24 hours.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[CH2:19]([N:31]1[C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[C:19]=2[N:18]=[C:17]1[CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)[C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)c2c(nc(C3CCNCC3)n2Cc2ccccc2)c2ccccc21
Yield: 189.5 %

Procedure:
As described in example 3F, a solution of 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (43 mg, 0.085 mmol) in EtOH was hydrogenated over 10% Pd/C (41 mg, 0.038 mmol) at 1 atm to give 3-benzyl-5-methyl-2-piperidin-4-yl-3,5-dihydro-imidazo[4,5-c]quinolin-4-one (30 mg, 95%). A solution of the amine in EtOAc was treated with HCl (1 M in diethyl ether) to prepare the HCl salt. 1H-NMR (DMSO): δ 8.12 (d, 1H, J=6.4 Hz), 7.57 (m, 2H), 7.30 (m, 3H), 7.24 (m, 1H), 7.14 (m, 2H), 5.86 (s, 2H), 4.08 (m, 1H), 3.67 (s, 3H), 3.31 (m, 3H), 2.93 (m, 2H), 2.0 (m, 2H) 1.71 (m, 2H). MS: calculated for C23H24N4O+H 373.2; found: 373.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2].[Br:26]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH2:11][Br:26])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 1-(2-chloro-phenyl)-5-(4-chloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester I-4a (2.8 g, 7.46 mmol), N-bromosuccinimide (1.6 g, 8.95 mmol), AIBN (245 mg, 1.49 mmol) in CCl4 (60 ml) was heated under reflux for 17 hours. The reaction was cooled to room temperature, filtered to remove any solids, and concentrated under vacuum. The crude residue was purified via silica gel chromatography (Flash 40) using a solvent gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to give the desired product (I-4b) as an amorphous solid (2.2 g, 64%): +APCI MS (M+1) 455.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[C:21]([C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][CH2:25][NH:26][CH:27]3[CH3:32])=[CH:20][CH:19]=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[CH:31][C:22]=4[C:21]4[C:16]([O:15][CH3:14])=[N:17][CH:18]=[CH:19][CH:20]=4)[CH:27]3[CH3:32])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncccc1-c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ncccc1-c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2-Methoxy-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: CC(O[CH2:5][C:6]1[C:11]2=[CH:12][CH:13]=[C:14](C=O)[C:10]2=[CH:9]OC=1)=O.C[N:18](C)CCCN>C(Cl)(Cl)Cl>[CH:9]1[NH:18][CH:5]=[CH:6][C:11]2[C:10]=1[CH:14]=[CH:13][CH:12]=2
Reactant: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reactant: CN(C)CCCN
Solvent: ClC(Cl)Cl
Product: c1cc2cc[nH]cc-2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Baldrinal (2) (12.8 mg) was reacted with 3-(dimethylamino)-1-propylamine (22.5 mg) in 2 ml of chloroform. After stirring for 10 minutes at room temperature, the solution turned red and all the baldrinal was reacted. Compound (9) was separated using column chromatography with silica using 50:1 CHCl3:MeOH solvent system and 2.2 mg of product was collected.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].C([O-])([O-])=O.[K+].[K+].[CH3:21][C:22]([CH3:24])=O>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:24][C:22]#[CH:21])=[CH:8][C:7]=1[CH3:13]
Reactant: CC(C)=O
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCOc1ccc(OCC(=O)OC)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (5.1 g, 25.8 mmol) and K2CO3 (7.1 g, 51.5 mmol) in acetone (85 ml) was added propagylbromide (3.1 g, 25.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 days, and then filtered and evaporated in vacuo. The residue was purified on column chromatography using methylene chloride as eluent to give the title compound in 6.0 (100%) yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:37]3[C:38]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc(F)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)C.C1COCC1>[OH:13][CH:12]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[OH:3]
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(O)c2ccccc2)c(O)c1

Procedure:
Sodium borohydride is dissolved in 75 ml of ethanol, and the starting material (2-hydroxy-4-methoxyphenyl)phenylmethanone, dissolved in 5 ml of THF, is added dropwise over the course of about 10 min. The reaction mixture is stirred at room temperature for 1 h until all the sodium borohydride has been consumed. The solvent is removed in vacuo. The residue is partitioned in methyl t-butyl ether (MTBE)/water, and the aqueous phase is extracted a further 3 times with 50 ml of MTBE. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo.
Reaction SMILES: [OH-].[Na+:2].[NH2:3][C@H:4]([C:9]([OH:11])=[O:10])[CH2:5][C:6]([OH:8])=[O:7]>O.CC(C)=O>[NH2:3][C@H:4]([C:9]([O-:11])=[O:10])[CH2:5][C:6]([O-:8])=[O:7].[Na+:2].[Na+:2]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]

Procedure:
Sodium hydroxide 8 g was added to a suspension of 13.3 g L-aspartic acid in 72 ml water and 48 ml acetone to form a solution of disodium L-aspartate. This solution was held at 0°C, and the solution of palmitic acid-sulfuric acid mixed acid anhydride and a solution of 12 g sodium hydroxide in 30 ml water was added dropwise simultaneously with stirring. This solution was stirred for 1 hour at 0°C.
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][N:26]1[CH:30]=[C:29]([S:31](Cl)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[C:29]([S:31]([N:12]2[C:13]3[C:9](=[C:8]4[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]4=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)(=[O:33])=[O:32])[N:28]=[C:27]1[CH3:35]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)cn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 1,2-dimethylimidazole-4-sulfonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (5 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 361 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:25][CH:5]1[CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl [4-(8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 4) in 5 mL MeOH at 0° C. was added NaBH4(18.0 mg, 0.48 mmol). The reaction was stirred at 0° C. for 2 hours and then quenched by the addition of H2O. The solution was diluted with Et2O and washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and the solvents were removed under reduced pressure. Column chromatography (20-40% EtOAc-hexanes) afforded 140.0 mg (87%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>C1(C)C=CC=CC=1.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>[CH2:24]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][CH:7]=1)[CH:23]=[CH2:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Yield: 346 %

Procedure:
5-Bromo-3-(1-BOC-2-(S)-pyrrolidinylmethoxy)pyridine (948 mg, 2.66 mmol) in toluene (10 mL) was added tetrakis(triphenylphosphine)palladium (15 mg) and allyltributyltin (0.18 mL, 0.56 mmol). The mixture was stirred and refluxed for two days. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (617 mg, 73%): 1H NMR (CDCl3, 300 MHz) δ 1.96 (m, 1H), 2.04-2.20 (m, 2H), 2.28 (m, 1H), 3.42 (t, 2H, J=7.0 Hz), 3.54 (d, 2H, J=7.0 Hz), 4.14 (m, 1H), 4.31 (dd, 1H, J=8.0, 10.5 Hz), 4.51 (dd, 1H, J=3.5, 10.5 Hz), 5.12-5.22 (m, 2H), 6.02 (m, 1H), 7.77 (s, 1H), 8.23 (s, 1H), 8.30 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/e 219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[C:12]#N.[H-].C([Al+]CC(C)C)C(C)C.C(C1C([O:34]C)=NC(C)=CC=1)#N>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:14])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[CH:12]=[O:34]
Reactant: Cc1nc(Cl)c(C#N)c2c1CCCC2
Reactant: COc1nc(C)ccc1C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1nc(Cl)c(C=O)c2c1CCCC2

Procedure:
3-Chloro-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carboxaldehyde was prepared from 3-chloro-4-cyano-methyl-5,6,7,8-tetrahydroisoquinoline by reduction with diisobutylaluminium hydride following essentially the same procedure as that described in J. Org. chem., 1980, 45, 1354 for the reduction of 3-cyano-2-methoxy-6-methylpyridine. Pmr spectrum (CDCl3 ; δ in ppm): 1.79 (4H,m); 2.47 (3H,s); 2.59-3.18 (4H,m); 10.52 (1H,s).