Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:13][C:12]2[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:10][C:9]([Cl:20])=[N:8][C:7]=2[CH:6]=1)=O.[NH2:21][C:22]([NH2:24])=[S:23]>CCO>[Cl:20][C:9]1[N:10]=[C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:12]2[S:13][C:5]([C:3]3[N:21]=[C:22]([NH2:24])[S:23][CH:2]=3)=[CH:6][C:7]=2[N:8]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCO
Product: Nc1nc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cs1
Temperature: 70 °C

Procedure:
To a solution of 2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone (1.0 eq) dissolved in EtOH was added thiourea. Reaction mixture was heated at 70° C. until completed, then extracted in dichloromethane with saturated bicarbonate solution one time. The organic layer is dried, filtered and concentrated to yield the crude intermediate. This intermediate is purified by flash chromatography to yield 4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)thiazol-2-amine. MS (Q1) 413 (M+)
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:30])[NH:9][CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.Br[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41]>O>[C:3]([O:7][C:8](=[O:30])[N:9]([CH2:10][CH:11]1[C:20]2[C:15](=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:37][CH2:38][CH2:39][CH:40]([CH3:42])[CH3:41])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC1CCCc2c(Oc3ccc(C#N)cn3)cccc21
Reactant: CC(C)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Add NaH (60% oil suspension, 30 mg, 0.750 mmol) to a solution of [5-(5-cyanopyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (Intermediate 22, 189 mg, 0.500 mmol) and DMF (5 ml) stirring at ambient temperature under nitrogen. After 20 minutes, add 1-bromo-4-methylpentane (247 mg, 1.50 mmol) and beat the mixture at 60° C. overnight. After cooling, pour the mixture into water and extract with EtOAc (2×). Wash the extract with water and brine before drying ((MgSO4) and concentrating. Purify on silica gel (20% EtOAc/Hexane) to obtain 111 mg of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)carbamic acid tert-butyl ester as a colorless glass.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12][C:11]1=2.N1C2C(=CC=CC=2)CCC1C.[Cl-].[NH4+]>C(OCC)C>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12][C:11]1=2
Reactant: Cc1ccc2c(n1)CCCC2=O
Reactant: Br[Mg]c1ccccc1
Agent: CC1CCc2ccccc2N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc2c(n1)CCCC2(O)c1ccccc1

Procedure:
To a stirred solution of 0.155 moles of phenylmagnesium bromide in 250 ml of diethyl ether was added dropwise a solution of 2.0 g (0.124 mole) of 5-keto-5,6,7,8-tetrahydroquinaldine in 100 ml of diethyl ether. After all of the tetrahydroquinaldine had been added the mixture was then treated with an excess of a saturated aqueous ammonium chloride solution. The ether layer was separated, dried and evaporated to prevent a residue. This residue was dissolved in dilute hydrochloric acid and the aqueous acid layer was then extracted sequentially with diethyl ether and hexane. The acid layer was then basified with aqueous sodium hydroxide. Filtration provided yellow solid 5-hydroxy-5-phenyl-5,6,7,8-tetrahydroquinaldine, which had a m.p. of 130°-134° C. after recrystallization from a dichloromethane-hexane mixture. Analysis: Calculated for C16H17NO: %C, 80.3; %H, 7.2; %N, 5.9; Found: %C, 80.2; %H, 7.2; %N, 5.5. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: CO[C:3](=[O:23])[C:4]([C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[CH:15]=1)=[CH:5][NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:21][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[CH3:20])[C:13]([C:4]1[C:3](=[O:23])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][N:9]=2)[NH:6][CH:5]=1)=[O:22]
Reactant: COC(=O)C(=CNc1cccnc1)C(=O)c1ccc(C)c(C)c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Temperature: 250 °C
Yield: 66.7 %

Procedure:
1.12 g (3.61 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(pyridin-3-ylamino)-acrylic acid methyl ester was dissolved in 30 mL of diphenyl ether and the solution was heated at 250° C. After 2.5 h the solution was cooled to rt and 50 mL of hexane was added. The mixture was filtered and the solid washed with hexane to yield 0.67 g of 3-(3,4-Dimethyl-benzoyl)-1H-[1,5]naphthyridin-4-one as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.Cl[CH2:12][CH:13]=O.C(=O)(O)[O-].[Na+].C>O.C1C=CC=CC=1>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]2[CH:12]=[CH:13][N:1]=[C:2]2[CH:7]=1
Reactant: COc1nc(N)cc(Cl)n1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1nc(Cl)cc2nccn12
Temperature: 80 °C

Procedure:
A mixture of 1.7 g (0.011 mole) of 4-amino-6-chloro-2-methoxypyrimidine and 3.0 g (0.015 mole) of 50% aqueous chloroacetaldehyde in 20 ml of water was heated at 80° C. for one hour, and was then cooled in an ice bath with concomitant neutralization with sodium bicarbonate. The mixture was extracted with three 50 ml portions of chloroform which were then dried over magnesium sulfate and evaporated. The residue obtained was dissolved in boiling benzene, treated with decolorizing charcoal, and filtered. The residue which was obtained by evaporation of the filtrate was triturated with diethyl ether to provide a yellow solid. The solid was purified on a preparative scale high pressure liquid chromatograph, using a mixture of 75% ethyl acetate/25% hexanes as the eluent. Recrystallization from cyclohexane gave white solid 7-chloro-5-methoxyimidazo[1,2-c]pyrimidine, m.p. 115°-118° C. Analysis: Calculated for C7H6H3OCl: %C,45.8; %H, 3.3; %N, 22.9; Found: %C, 45.4; %H, 3.1; %N, 23.4.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[H-].[Na+].[C:17]([O:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=[O:20])[CH2:18][CH3:19]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([N:22]([O:21][C:17](=[O:20])[CH2:18][CH3:19])[C:23](=[O:24])[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:13])=[O:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCC(=O)ONC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)ON(C(=O)OCc1ccccc1)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
Benzyl {[2-(methylsulfonyl)phenyl]sulfonyl}(propanoyloxy)carbamate (51) is prepared from 2-methylsulfonylbenzenesulfonyl chloride, sodium hydride and [(benzyloxy)carbonyl]-amino propanoate according to Scheme 2. (0.56 g, 50%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.39 (1H, d, 7.9 Hz), 8.35 (1H, d, 7.9 Hz), 7.80-7.86 (1H, m), 7.68-7.73 (1H, m), 7.30-7.39 (3H, m), 7.18-7.23 (2H, m), 5.17 (2H, br. s.), 3.30 (3H, s), 2.58 (2H, br. s.), 1.23 (3 H, t, 7.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][NH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: Cc1cccc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc2c(Cl)ncnc12
Temperature: 120 °C
Yield: 90 %

Procedure:
POCl3 (300 mL) was taken in a 2 L round bottom flask under nitrogen. To this was added 8-Methylquinazolin-4(3H)-one (45 g) in portions. The reaction mixture refluxed at 120° C. for 12 h. Reaction completion was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The resulted residue was dissolved in DCM (500 mL) and quenched slowly into an ice cold solution of saturated K2CO3 with constant stirring. Then the organic layer was separated and washed with brine solution, dried over sodium sulphate and concentrated under vacuum to afford (45 g, 90% yield) of the titled compound as yellow solid. This was taken for next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 9.03 (s, 1H), 8.08-8.06 (dd, J=8.9, 8.4 Hz, 1H), 7.77-7.76 (d, J=7.1 Hz, 1H), 7.59-7.56 (d, J=15.5 Hz, 1H), 2.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1Br
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc(-c2cccc(N)c2C#N)c1
Yield: 80.3 %

Procedure:
To a stirred solution of 2-amino-6-bromobenzonitrile (195 mg, 1.0 mmol) and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165° C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH:7](OC)OC)[CH3:2].Cl.[OH-].[Na+].[C:40](OCC)(=[O:42])C.CCCCCC>CC(C)=O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:25]2[C:20](=[CH:21][C:22]([O:34][CH3:35])=[C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:24]=2)[CH:12]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:42][CH3:40])[CH:19]=1)=[O:36])[CH3:2]
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)N1C=Cc2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (100 mg, 0.19 mmol) in acetone (5 mL) was added 6N hydrochloric acid (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 hrs and neutralized by addition of 6N aqueous sodium hydroxide solution. The solvent was evaporated and the aqueous phase was extracted with dichloromethane (3×25 μL). The combined extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (60 g, 85% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH2:20][F:19])=[CH:27][N:26]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(OCF)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCF)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-fluoromethoxy-pyridine-2-carboxylic acid (CAS1174321-03-9, WO2009091016) following procedure I yielded the title compound as a colorless oil. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Reactant: CC(C)(O)CN
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NCC(C)(C)O)cn1
Yield: 17 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 1-amino-2-methyl-propan-2-ol instead of 2,2,2-trifluoroethylamine, to the title compound (40 mg, 17%) which was obtained as a colourless oil. MS: m/e=418.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[NH:21][CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1c[nH]c2ccccc12

Procedure:
A solution of 20.2 g. (0.070 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 8.8 g. (0.075 mol.) of indole in 300 ml. of toluene was slowly distilled over a 30 minute interval with periodic replacement of the toluene with fresh solvent. After an additional 45 minutes the reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was triturated with hexane to give α-(N-t-butoxycarbonylamino)indole-3-acetic acid n-butyl ester, m.p. 127°-128° (ether-hexane).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[O:23]1[C:34]2[C:35]3[C:30]([C:31](B(O)O)=[CH:32][CH:33]=2)=[N:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]1>>[O:23]1[C:34]2[C:35]3[C:30]([C:31]([C:2]4[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]5[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]5)[N:3]=4)=[CH:32][CH:33]=2)=[N:29][CH:28]=[CH:27][C:26]=3[CH2:25][CH2:24]1
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c3c(ccnc13)CCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:19](=O)[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:19]([NH2:28])[CH3:20])=[CH:10][C:11]([CH3:18])=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc(C)c2cccnc2c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1cc(C(C)N)c(-c2cccc(F)c2)c2ncccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[8-(3-fluorophenyl)-5-methylquinolin-7-yl]ethanone (50 mg, 0.2 mmol) and ammonium acetate (138 mg, 1.79 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (22.5 mg, 0.358 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C18H18FN2 (M+H)+: m/z=281.1; Found: 281.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10](Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.N1([C:23]2[C:24](=[O:38])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH:28]=2)CCOCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11]([C:10]1[C:28]2[CH2:27][CH2:26][N:25]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=3)[C:24](=[O:38])[C:23]=2[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)=[O:12])[CH3:15]
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(Cl)=NNc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(-c2cccc(Cl)c2)c2c1CCN(c1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 80 °C
Yield: 47.6 %

Procedure:
Part A: A 500 mL flask was charged with N-(3-chlorophenyl)-1-(ethoxycarbonyl)-methanehydrazonoyl chloride (3.67 g, 14.1 mmol), 3-morpholin-4-yl-1-(4-nitro-phenyl)-5,6-dihydro-1H-pyridin-2-one (2.14 g, 7.05 mmol), 50 mL of toluene, and triethylamine (3.57 g, 35.3 mmol). The mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was treated with trifuloroacetic acid (10.1 g) at rt for 5 h. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride, washed water and brine, and dried with sodium sulfate. The crude product, after evaporation of the solvent, was purified by silica gel chromatography, eluting with 1:2 ethyl acetate/hexane to yield 1-(3-chloro-phenyl)-6-(4-nitro-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (1.48 g). 1H NMR (300 MHz, CDCl3) δ 8.24 (2H, d, J=9.1 Hz), 7.60 (1H, t, J=1.8 Hz), 7.52 (2H, d, J=9.1 Hz), 7.47˜7.36(2H, m), 4.48 (2H, q, J=7.0 Hz), 4.22 (2H, t, J=6.6 Hz), 3.39 (2H, t, J=6.6 Hz), 1.45 (3H, t, J=7.0 Hz) ppm.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:23]=O>C(O)=O>[CH3:23][NH:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=O
Reactant: NCCOc1c(-c2ccccc2)[nH]c(=O)c2ccccc12
Agent: Cl
Solvent: O=CO
Product: CNCCOc1c(-c2ccccc2)[nH]c(=O)c2ccccc12
Yield: 51.6 %

Procedure:
To a solution of 25 mg (0.079 mmol) of 4-(2-amino-ethoxy)-3-phenyl-2H-isoquinolin-1-one hydrochloride (cmpd. 1) in formic acid (0.1 mL), 8 μL (0.08 mmol) of formaldehyde (37% in water) were added and the mixture was refluxed for 1 hour. The solvent was concentrated under reduced pressure and the resulting crude was purified by preparative HPLC affording 12 mg of the title compound (51%).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:14]O>>[CH3:14][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH:6][CH2:7][CH3:8]
Reactant: CCC=C(C)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCC=C(C)C(=O)OC
Temperature: 20 °C
Yield: 91 %

Procedure:
A mixture of 2-methylpent-2-enoic acid (5.0 g, 44 mmol) and sulfuric acid (0.5 mL) in methanol (250 mL) was heated at reflux for 16 hours. The solution was allowed to cool down to 20° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.1 g, 91%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:30]O)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(C)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:30][Br:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCCCCCCCOCC(CO)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CBr)OCc1ccccc1

Procedure:
In a 250 ml round bottom flask equipped with a magnetic stir bar, 2.00 g (4.6 mmoles) of 1-O-octadecyl-2-O-benzyl-glycerol (Bachem, Switzerland) was dissolved into 120 ml of toluene. To this solution were added 4.58 g. (13.8 mmoles) of carbon tetrabromide and 3.62 g. (13.8 mmoles) of triphenylphosphine and the reaction mixture stirred for 4 hours at room temperature. The yellow suspension was filtered and the filtrate concentrated on a rotary evaporator to afford a white solid. This residue was dissolved into 50 ml chloroform, washed twice with 30 ml saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under vacuum on a rotary evaporator to afford 2.5 g of the crude product as a white powder. This crude product was purified by flash column chromatography on a silica gel 60 (E. Merck, Germany) column by sequential elution with 100 ml each of hexane, 1% ethyl acetate in hexane, 2% ethyl acetate in hexane and finally with 3% ethyl acetate in hexane. Fractions collected were screened by TLC and those fractions that contained pure product (silica gel, 5% ethyl acetate in hexane, Rf=0.56) were pooled. The pooled fractions were concentrated under vacuum on a rotary evaporator to afford a quantitative yield of the 1-O-octadecyl-2-O-benzyl-3-bromo-1,2-propanediol as a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20](Cl)=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=3[O:40][CH3:41])=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CC(C)C(=O)N2C
Yield: 51.8 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-42), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.046 g (0.00024 mole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0451 g of (rac)-4-(9-benzyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-42) as white powder. HRMS (ES+) m/z Calcd for C30H37N7O3+H [(M+H)+]: 544.3031. Found: 544.3031.