Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].Cl.[CH3:18][C:19]1[CH:20]=[C:21]([CH:26]=[C:27]([CH3:29])[N:28]=1)[C:22]([NH:24][NH2:25])=O>>[CH2:1]([C:3]1[S:7][C:6]([C:8]2[O:10][C:22]([C:21]3[CH:26]=[C:27]([CH3:29])[N:28]=[C:19]([CH3:18])[CH:20]=3)=[N:24][N:25]=2)=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2]
Reactant: Cc1cc(C(=O)NN)cc(C)n1
Reactant: CCc1sc(C(=O)O)c2c1CC(C)(C)CC2
Agent: Cl
Product: CCc1sc(-c2nnc(-c3cc(C)nc(C)c3)o2)c2c1CC(C)(C)CC2

Procedure:
4-[5-(3-Ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-pyridine is synthesized from 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid and 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride in analogy to Example 9; LC-MS: tR=0.93 min, [M+1]=368.44; 1H NMR (CD3OD): δ 7.66 (s, 2 H), 3.09 (t, J=6.7 Hz, 2 H), 2.80 (q, J=7.6 Hz, 2 H), 2.60 (s, 6 H), 2.39 (s, 2 H), 1.67 (t, J=6.7 Hz, 2 H), 1.29 (t, J=7.6 Hz, 3 H), 1.03 (s, 6 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]1=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][N:26]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:10]([CH3:9])[C:11](=[O:34])[CH:12]=[CH:13]3)[CH:29]=1
Reactant: O=Cc1cccnc1
Reactant: Cn1c(=O)ccc2cc(OCCCCCNCc3cccnc3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1c(=O)ccc2cc(OCCCCCN(Cc3cccnc3)Cc3cccnc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine-3-carbaldehyde (0.076 ml) was added to a 1,2-dichloroethane solution (3 ml) of 1-methyl-6-{5-[(pyridin-3-ylmethyl)-amino]-pentyloxy}-1H-quinolin-2-one (237 mg). The mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.23 g) was added to the mixture, and the mixture was stirred at room temperature for 3 days. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, followed by extraction using dichloromethane. The organic layer was dried with anhydrous sodium sulfate, and condensed under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:hexane=1:1). The purified product was condensed under reduced pressure to give the title compound (247 mg) as a yellow oil.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:27])[C@@H:6]([NH:11][C@@H:12]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].[CH3:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)(=[O:31])=[O:30].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([CH2:3][NH:4][C:5](=[O:27])[C@H:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:11][C@H:12]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:20]1[CH:25]=[CH:24][C:23]([C:35]2[CH:36]=[CH:37][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=2)=[CH:22][CH:21]=1)#[N:2]
Reactant: CC1(C)OB(c2ccc(S(C)(=O)=O)cc2)OC1(C)C
Reactant: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1)C(=O)NCC#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N[C@H](c1ccc(F)cc1)c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(=O)NCC#N
Temperature: 82.5 °C

Procedure:
A mixture of (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentanoic acid cyanomethylamide (0.27 g, 0.636 mmol), 2-(4-methanesulfonylphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.177 g, 0.626 mmol) and potassium carbonate (0.703 mL of a 2.0 M solution) in DMF (5 mL) was degassed. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (27 mg, 0.038 mmol) was added. The reaction mixture was heated in a sealed tube at 80-85° C. for 3 hours and cooled to room temperature. Ethyl acetate (15 mL) was added. The reaction mixture was washed with brine (10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL), filtered through a plug of MgSO4/DARCO activated charcoal/silica gel, concentrated in vacuo, and purified by preparative TLC (Chromatotron® using 5% ethyl acetate/dichloromethane to elute to give N1-(cyanomethyl)-N2-{(S)-(4-fluorophenyl) [4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]methyl}-L-leucinamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[N:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:11][C:8]2[N:9]=[C:10]3[C:2]([Cl:1])=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2nc(N)cnc21
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Yield: 31 %

Procedure:
7-Chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (100 mg, 0.335 mmol) was dissolved in 1,2-dichloroethane (3.4 mL). Cyclohexylisocyanate (0.43 mL, 3.35 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, and concentrated. The residue was dispersed in 3 mL of toluene, cyclohexylisocyanate (0.86 mL, 6.70 mmol) was added and the reaction mixture was heated to reflux overnight, and cooled to 0° C. The precipitates were filtered, washed with toluene and dried under high vacuum to give 44 mg of 1-cyclohexyl-3-[7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid (31% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[NH:7][C:8](=[O:10])[CH3:9])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][CH2+:36]1SC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[C:39](=[O:40])[C:38](=[C:41]2[N:45]([CH3:46])[C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[S:42]2)[S:37][C:36]1=[N:14][C:13]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1cc(NC(C)=O)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1cc(NC(C)=O)ccc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 3′-ethylamino-4′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.45-7.53 (3H, m), 7.27-7.37 (4H, m), 7.17 (1H, m), 7.03-7.09 (2H, m), 6.91 (1H, d), 6.83 (1H, br d), 6.75 (1H, br s), 5.18 (2H, s), 3.78 (3H, s), 2.99 (2H, m), 2.15 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:27])([F:26])[F:25])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH2:17])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28]I>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:24]([F:26])([F:25])[F:27])/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[C:16]([CH:18]=2)[NH:17][CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: CI
Solvent: ClCCl
Product: CNc1cc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
To a stirred solution of (E)-5-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(1H-1,2,4-triazol-1-yl)aniline (0.3 g, 0.7 mmol) in CH2Cl2 (10 mL) was added TEA (0.155 mL, 1.09 mmol) and methyl iodide (0.124 g, 0.873 mmol). The reaction was stirred at ambient temperature for 18 h. The CH2Cl2 layer was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 50% EtOAc/Pet ether) to afford the title compound as a yellow semi-solid (0.07 g, 70%).
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]>C(Cl)Cl.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:3][Si:2]([CH3:4])([CH3:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:2]([Cl:3])([CH3:4])[CH3:1]
Reactant: C=CCCCCC=C
Reactant: C[SiH](C)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: C[Si](C)(Cl)CCCCCCCC[Si](C)(C)Cl
Reaction time: 3 h
Yield: 60 %

Procedure:
Dimethylchlorosilane (6.8 mL, 60 mmol) in CH2Cl2 (10 mL) was added by dropping funnel over 10 minutes to a mixture of 1,7-octadiene (4.5 mL, 30 mmol) and bis(tetrabutylammonium)hexachloroplatinate (272 mg, 0.3 mmol). After 3 hours at room temperature, the solvent was removed in vacuo and the residue taken up in pentane. The majority of the catalyst was removed by filtration under nitrogen and the filtrate was concentrated in vacuo to provide as an oily liquid 1,8 bis(chlorodimethyl silyl) octane 1H NMR (200 MHz, CDCl3)δ 1.94-1.75 (m,10H), 0.80 (t,4H), 0.40 (s.12H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:4][CH:3]=1.[C:18]1([OH:24])C=CC=C[CH:19]=1.ClC1C=CC(Cl)=CC=1C(Cl)=O.C(Cl)(=O)C>>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:6][CH:7]=1)(=[O:24])[CH3:19]
Reactant: Oc1ccccc1
Reactant: O=C(c1ccc(O)cc1)c1cc(Cl)ccc1Cl
Agent: O=C(Cl)c1cc(Cl)ccc1Cl
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc(C(=O)c2cc(Cl)ccc2Cl)cc1

Procedure:
4'-Acetoxy-2,5-dichlorobenzophenone is prepared by treating 4'-Hydroxy-2,5-dichlorobenzophenone, which is prepared by the Friedel-Crafts acylation of phenol with 2,5-dichlorobenzoyl-chloride, with acetyl chloride.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([N:15]4[CH2:20][CH2:19][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH3:24])[CH2:17][CH2:16]4)=[N:12][C:11]=3[CH:33]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[C:35](OCC)(=O)C>>[CH:1]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([N:15]4[CH2:16][CH2:17][CH:18]([O:21][CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[CH3:35])[CH3:24])[CH2:19][CH2:20]4)=[N:12][C:11]=3[CH:33]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(C)=O
Reactant: C[C@@H](COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CC(=O)N[C@@H](C)COC1CCN(c2nc3cc(OCC4CCC4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To tert-butyl [(1S)-2-({1-[5-(cyclobutylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)-1-methylethyl]carbamate (380 mg) was added 4M hydrogen chloride/ethyl acetate (5 mL), and the mixture was stirred at room temperature for 15 min and concentrated. Pyridine (5 mL) and acetic anhydride (5 mL) were added to the residue, and the mixture was stirred at room temperature for 10 min. After concentration, the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate), and the obtained solid was washed with diethyl ether to give the title compound (158 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17]Cl)(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][NH:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[C:31]([O:32][CH3:33])[CH:30]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([CH2:15][CH2:16][CH2:17][N:26]([CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[C:31]([O:32][CH3:33])[CH:30]=2)[CH3:25])(=[O:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1cc(NS(=O)(=O)CCCCl)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: COc1cc(NS(=O)(=O)CCCN(C)CCc2ccc(OC)c(OC)c2)cc(OC)c1
Reaction time: 72 h

Procedure:
N-(3,5-Dimethoxyphenyl)-3-chloro-1-propanesulfonamide prepared in the preceding paragraph (16.56 g, 0.057 mol) was dissolved in xylene (300 mL) containing potassium carbonate (7.86 g, 0.057 mol) and N-methylhomoveratrylamine (11.13 g, 0.057 mol) and the reaction warmed and stirred three days. Filtration, stripping of solvent and chromatography on dry-column silica gel (1100 g) with 5% methanol/ethyl acetate provided crude N-(3,5-dimethoxyphenyl)-3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]-1-propanesulfonamide (5.32 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(OC2CCCCC2)(=O)=O)=[CH:13][CH:12]=1.[I-].[K+].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[F:10][C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([O:8][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCCC2)cc1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cc(OC2CCCCC2)c(Cl)cc1F
Temperature: 100 °C
Yield: 48.1 %

Procedure:
A round-bottomed flask (100 cc) equipped with a mechanical stirrer was charged with 5-amino-2-chloro-4-fluorophenol (1.03 g, 6.40 mmol), cyclohexyl p-toluenesulfonate (1.69 g, 6.66 mmol), tetrabutylammonium bromide (124 mg, 0.38 mmol) and potassium iodide (100 mg, 0.60 mmol) to prepare a solution in toluene (15 mL). Subsequently, 40% sodium hydroxide in aqueous solution (15 mL) was added slowly and the mixture was stirred under heating at 100° C. for 48 h. After completion of the reaction, the reaction mixture was cooled to room temperature and water (10 mL) was added, followed by extraction with ethyl acetate (20 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give a crude product (1.06 g). The product was separated and purified by silica gel column chromatography (ethyl acetate/hexane=1/9) to give 2-fluoro-4-chloro-5-cyclohexyloxyaniline (0.75 g, 3.08 mmol; yield=48.1%). 1H-NMR(CDCl3,TMS,ppm): δ1.15-2.06(10H,m), 3.46(2H, brs), 3.95-4.25(1H,m), 6.39 (1H,d,JHF =9.0HZ), 6.97(1H,d,JHF =11.5HZ). IR (neat, cm-1): 3500, 3400, 2940, 2860, 1630, 1505, 1240, 1190.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[NH:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:22][O-].[Na+].CI.O>CN(C)C=O.CO>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:21])[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[N:14]([CH3:22])[C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)Nc1cccc2c(=O)[nH]c3ccccc3c(=O)c12
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc2c(=O)n(C)c3ccccc3c(=O)c12
Reaction time: 0.5 h

Procedure:
To 2 g 10-acetamido-5,6-dihydro-11H-dibenzo(b,e)azepine-6,11-dione suspended in 20 ml dimethylformamide are added 710 mg sodium methylate in 10 ml methanol. After keeping at ambient temperature for 30 minutes, 2.5 ml methyl iodide are added and the mixture then kept at ambient temperature for 24 hours. It is then poured into water, filtered, dried and crystallized from ethanol: yield 1.6 g, melting point 203°-204° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:18]
Reactant: O=C(Br)CBr
Reactant: COC(=O)/C=C(/C)N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)/C=C(/C)NC(=O)CBr
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
A mixture of methyl 3-aminocrotonate (3.20 g, 27.79 mmol) and pyridine (2.64 g, 33.33 mmol) in CH2Cl2 (60 mL) was stirred at −20° C. for 20 min. To the mixture was added a solution of bromoacetyl bromide (5.61 g, 27.79 mmol) in CH2Cl2 (20 mL) dropwise. The mixture was stirred at rt for 2 h. The organic phase was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=5:1) to give the title compound as a reddish solid (0.99 g, 15%).
Reaction SMILES: CN(C)C=O.[CH3:6][C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1.CS(O[CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH3:6][C:7]1[C:12]([C:13]([O:15][CH2:27][CH2:28][C:29]([CH3:33])=[C:30]([F:32])[F:31])=[O:14])=[CH:11][N:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]=1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Reactant: Cc1nc(-c2ccccc2)ncc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCOC(=O)c1cnc(-c2ccccc2)nc1C)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.34 g (1.6 mmol) of 4-methyl-2-phenylpyrimidine-5-carboxylic acid, synthesized in accordance with a method described in “J. Chem. Soc.”, page 2183 (1923), and 0.30 g (1.5 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.27 g (3.2 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethtyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:4) to obtain 0.35 g (yield: 73%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-phenylpyrimidine-5-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([O-:27])=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([OH:27])=[O:26])=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)[O-])c3n2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Yield: 73.5 %

Procedure:
Crude 2-(2-(2-(bis(tert-butoxycarbonyl)amino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetate (240 mg) was reacted with 3 eq of lithium hydroxide in 1:1 THF/water solution. After completion, the THF was concentrated in vacuo and the water solution was acidified to pH 2 using a concentrated HCl solution. The product precipitated as a fine white solid and was filtered to yield 2-(2-(2-(tert butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (145 mg), of which 40 mg was subjected to General Procedure E and purified via reverse phase HPLC to give 19.5 mg 125 as a white solid. MS (Q1) 357.2 (M)+
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzyl alcohol in 150 ml of CHCl3 is added dropwise 7.5 ml of thionyl chloride during 10 min. The reaction mixture is stirred for 4 hours at room temperature, and then washed with NaHCO3 solution. The organic solution is separated, dried, and evaporated to 3-(2-quinolinylmethyloxy)benzyl chloride which is used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=2)[C:9]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[N:8][C:7]1=[O:29].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.O.C(Cl)Cl>C(Cl)Cl>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[CH:32]=[CH:31][CH:30]=[C:4]([CH2:5][N:6]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]#[CH:19])=[CH:13][CH:14]=3)[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:27])[CH3:28])=[CH:22][CH:21]=3)=[N:8][C:7]2=[O:29])[CH:3]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(N)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1cccc(NC(=O)CCl)c1
Yield: 95.7 %

Procedure:
A solution of 200 mg (0.47 mmol) 1-(3-amino-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one in 3 ml CH2Cl2 is treated at 0° C. with 41 μl (0.52 mmol; 1.1 eq.) chloroacetyl chloride and 79 μl (0.57 mmol; 1.2 eq.) triethylamine. The mixture is allowed to come to rt. Extractive work-up with water/CH2Cl2 yields 225 mg (95%) of a yellow solid. m.p. 170-172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[C:21]([O:23]C)=[O:22].[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[C:21]([OH:23])=[O:22]
Reactant: COC(=O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(C(=O)O)n(C)c(=O)c3ccccc23)c(C)c1

Procedure:
A mixture of methyl 4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylate (30 g, 74.7 mmol) in tetrahydrofuran (THF) (400 mL) was treated with lithium hydroxide (8.94 g, 373 mmol) and stirred at reflux overnight. The mixture was concentrated and used crude in the next step (21.6 g, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.81-14.14 (m, 1 H) 8.28-8.37 (m, 1 H) 7.62-7.69 (m, 1 H) 7.53-7.61 (m, 1 H) 7.13-7.19 (m, 1 H) 7.01-7.12 (m, 2 H) 6.82-6.91 (m, 1 H) 3.52 (s, 3 H) 2.34 (s, 3 H) 1.97 (s, 3 H); LC/MS (m/z) ES+=308 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH2:16][C:17](=O)[CH3:18])(=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(=O)C>[CH3:18][C:17]1[CH:16]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]2[N:4]=[C:5]([NH2:7])[N:6]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: Nc1n[nH]c(N)n1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)n2nc(N)nc2n1

Procedure:
A mixture of 14 g (141.4 mmol) of 3,5-diamino-1,2,4-triazole and 24.0 g (148.1 mmol) benzoylacetone was heated in 200 ml of glacial acetic acid at reflux for 2 hours. A solution soon formed after heating. The solvent was removed in vacuo and the residue dissolved in 400 ml of methylene chloride which was then washed with water (2X), brine and dried over magnesium sulfate. The solution was concentrated in vacuo (not to complete dryness) and ethyl acetate added to the residue. The precipitated solid was filtered and washed with ethyl acetate to give 16.0 g of reasonably pure intermediate 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidin-2-amine which was able to be taken on directly to the next step without further purification m.p. 246°-250° .