Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[N:38]1[N:39]([C:43]2[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=2[C:45](O)=[O:46])[N:40]=[CH:41][CH:42]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:45]([C:44]4[CH:48]=[CH:49][CH:50]=[CH:51][C:43]=4[N:39]4[N:40]=[CH:41][CH:42]=[N:38]4)=[O:46])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: O=C(O)c1ccccc1-n1nccn1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. Additionally, the reaction time was shortened to 30 minutes. MS (ESI) mass calcd. for O22H−23F3N8O, 472.47; m/z found 473 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.19-6.80 (m, 7H), 4.49-3.78 (m, 5H), 3.75-3.30 (m, 2H), 3.22-3.10 (m, 2H), 3.06-2.74 (m, 5H), 2.24-1.87 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.[CH3:17][N:18]([CH3:27])[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>CS(C)=O.O>[C:15]([C:12]1[S:11][C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH2:2][N:24]3[CH2:23][CH2:22][N:21]([C:19]([N:18]([CH3:27])[CH3:17])=[O:20])[CH2:26][CH2:25]3)[CH:8]=[CH:7][N:6]=2)=[N:14][CH:13]=1)#[N:16]
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Reactant: CN(C)C(=O)N1CCNCC1
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.119 g, 0.47 mmol) was dissolved in 1 mL DMSO. N,N-Dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 3.5 hr. Additional N,N-dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 1.5 hr. The reaction was diluted with water and the resulting precipitate collected by filtration. The solid was washed with water and hexanes then air dried overnight to afford the free base. Free base: 1H NMR (CD3OD) δ 8.33 (d, 1H, J=5.0 Hz), 8.03 (s, 1H), 7.08 (s, 1H), 7.04 (d, 1H, J=5.0 Hz), 3.58 (s, 1H), 3.29 (t, 4H, J=6.0 Hz), 2.84 (s, 6H), 2.49 (t, 4H, J=Hz). MS [M+H]+=372.1611.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:39])([F:38])[F:37]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(=O)(=O)NC(C)(C)C)cc4)c3)n2)ccc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(S(N)(=O)=O)cc4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.057 g) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (2.5 mL) and MeOH (2.5 mL) were added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/heptane/MeOH) to yield the title compound as a white solid (0.038 g, 7%). MS (ISN) 526.5 [(M−H)−]; mp 287° C.
Reaction SMILES: CN.Cl.[C:4]1([C:10]2([CH2:16][C:17](=O)[CH3:18])[CH:15]=[CH:14][CH2:13][CH:12]=[CH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([BH3-])#[N:21].[Na+]>CCOCC.CO>[CH3:18][CH:17]([NH:21][CH3:20])[CH2:16][C:10]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:14][CH2:13][CH:12]=[CH:11]1
Reactant: [BH3-]C#N
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CNC(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 0 °C

Procedure:
To 11.5 ml. (about 6 equivalents) of methylamine and 10 g. of molecular sieve 3A in 200 ml. of absolute methanol are added dropwise at 0° C. 17.8 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and subsequently 9.4 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of methanol. After the addition of 1.95 g. (0.75 equivalent) of sodium cyanoborohydride, the mixture is stirred at room temperature for 5 days. The mixture is worked-up as follows: The mixture is treated with ice-water and ether and extracted with 3 N aqueous hydrochloric acid. The hydrochloric acid extracts are made basic with concentrated aqueous ammonia and extracted with ether. The ether phase is dried with sodium sulfate, filtered and evaporated. The crude product obtained is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained α,N-dimethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine in the form of an oily product. This is converted as usual into the hydrochloride which, after crystallization from methylene chloride/ether, has a melting point of 155°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][C:8](=[O:15])[CH:7]=[N:6]2.[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]([CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:33])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:26]1)[C:8](=[O:15])[CH:7]=[N:6]2
Reactant: COc1cc2ncc(=O)[nH]c2cc1OC
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2cc1OC
Yield: 27.6 %

Procedure:
6,7-Dimethoxyquinoxalin-2(1H)-one (Intermediate 158, 540 mg, 2.60 mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.9 mmol) as described for Intermediate 2. Chromatography on silica gel with 20-50% acetone in hexanes gave 310 mg (28%) of the product as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[CH2:9][CH2:10][N:11]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:12][CH2:13][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[O:7])[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[C:62]1([CH3:72])[CH:67]=[CH:66][C:65]([S:68](Cl)(=[O:70])=[O:69])=[CH:64][CH:63]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:68]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:13][CH2:12][N:11]([S:35]([C:38]1[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=1)(=[O:36])=[O:37])[CH2:10][CH2:9][N:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[S:45]([C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1)(=[O:46])=[O:47])([C:65]1[CH:66]=[CH:67][C:62]([CH3:72])=[CH:63][CH:64]=1)(=[O:70])=[O:69]
Reactant: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCOS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To 5.47 g of 16-butoxycarbonyl-10, 13,16-tri(p-toluenesulfonyl)-10, 13,16-triazahexadecanol in 200 ml of CH2Cl2, 2.95 g of Et3N was added and the mixture was cooled to 0° C. To the well stirred solution was added dropwise at 0° C. 0.22 g of 4-dimethylaminopyridine and then 1.67 g of p-toluenesulfonyl chloride in 100 ml of CH2Cl2 was added. The reaction was continued overnight at room temperature. A 0.04 g amount of 4-dimethylaminopyridine and 0.33 g of p-toluenesulfonyl chloride were added at 7° C. and stirring was continued for 4 hours. The mixture was extracted with water twice. The organic layers were dried over MgSO4, filtered and evaporated under reduced pressure and eluted with CH2Cl2 and CH2Cl2/ethyl acetate (100/1 v/v). About 4.21 g of product was obtained. The preparation scheme is shown below:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18](O)=[O:19].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[CH:16]=[CH:17][C:18]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1)=[O:19]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: Cc1cc(N)cc(C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C=CC(=O)Nc2cc(C)c(O)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Under argon gas stream, to a solution of 600 mg of 4-amino-2,6-dimethylphenol in 20 ml of tetrahydrofuran is added under ice-cooling 779 mg of 3-methoxycinnamic acid, and then 902 mg of dicyclohexylcarbodiimide and 118 mg of 1-hydroxybenzotriazole are added, followed by stirring at room temperature overnight. After ethyl acetate is added to the reaction mixture, the mixture is washed successively with 10 % hydrochloric acid, water, 5 % sodium hydrogen carbonate and water, and dried, followed by concentration. The residue is recrystallized from ethyl acetate-n-hexane to give 890 mg of 4-(3-methoxycinnamoyl)amino-2,6-dimethyl-phenol.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([OH:20])=O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:18]([NH:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])=[O:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:21]3[CH:26]=[C:25]([C:27](=[O:32])[NH:28][CH:29]4[CH2:31][CH2:30]4)[CH:24]=[CH:23][C:22]=3[CH3:33])[CH:14]=2)[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccc3)cc(C(=O)NCCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the product of step iii) (0.48 g) and N,N-dimethylethane-1,2-diamine (0.17 mL) in THF (20 mL) was added N,N-diisopropylethylamine (0.56 mL) followed by HATU (0.60 g) and the reaction stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the crude product purified by SiO2 chromatography (eluting with 90:10:0.1 dichloromethane:methanol:triethylamine). The fractions containing product were concentrated to dryness and the residue triturated with acetonitrile to give the title compound as a solid (0.35 g).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[NH:11][C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O1CCCC1.O>[F:28][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[CH2:15][CH2:16][C:17](=[O:18])[C:13]=3[CH:12]([C:19]3[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=3)[N:11]([S:32]([CH3:31])(=[O:34])=[O:33])[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 50 °C

Procedure:
4-(1-(3-(Difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 30 mg, 0.74 mmol) in tetrahydrofuran (3.0 mL). After 10 min methanesulfonyl chloride (42 μL, 0.55 mmol) is added and the mixture is heated at 50° C. over night. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 74 mg; ESI mass spectrum [M+H]+=458; Retention time HPLC: 0.76 min (005_CA01).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@H:8]([OH:10])[CH3:9])([CH3:4])[CH3:3].O[C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][C:2]([Si:5]([CH3:12])([CH3:11])[O:6][CH2:7][C@@H:8]([O:10][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:9])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 16 h
Yield: 80.1 %

Procedure:
(2R)-1-{[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}propan-2-ol (3.31 g, 17.4 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (3.00 g, 11.6 mmol) in THF (50 mL) at 0° C. followed by addition of triphenylphosphine (4.57 g, 17.4 mmol) then DIAD (3.43 mL, 17.4 mmol) and the reaction was warmed to RT and stirred for 16 h. The reaction was quenched with water (100 mL) and diethyl ether (400 mL) and the organic layer was separated then dried (MgSO4) and evaporated. Purification by column chromatography, eluting with 1:15 to 1:5 ethyl acetate:hexane, afforded the title compound as a colourless oil (4.00 g, 80%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[C:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:22]=[CH:23][C:24]([C:25]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:26])=[CH:28][CH:29]=1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ncccc21

Procedure:
A stirred mixture of 9,10-dihydro-4H-3a,5,9-triaza-benzo[f]azulene of Step D (0.54 mmol), 4-phenylbenzoylchloride (1.08 mmol) and triethylamine (1.08 mmol) in toluene was refluxed under nitrogen for 72 hours. The reaction was cooled and the solvent removed in vacuo. Chromatography of the residue over silica gel Merck-60 with a solvent gradient from 5 to 20% ethyl acetate in hexane provided the title compound as a tan solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:15][C:16]1[CH:17]=[C:18]([Cl:25])[C:19]([CH2:23]Br)=[C:20]([Cl:22])[CH:21]=1>CN(C=O)C.C(OCC)C>[Br:15][C:16]1[CH:17]=[C:18]([Cl:25])[C:19]([CH2:23][N:9]2[CH2:10][CH2:11][CH:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:8]2=[O:12])=[C:20]([Cl:22])[CH:21]=1
Reactant: O=C1NCCC1N1CCCCC1
Reactant: Clc1cc(Br)cc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1C(N2CCCCC2)CCN1Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.2 %

Procedure:
Treat a solution of 3-piperidin-1-yl-pyrrolidin-2-one (0.33 g, 1.96 mmol) in DMF (6 mL) with 60% sodium hydride (0.12 g, 3.00 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (0.70 g, 2.19 mmol), stir for 15 minutes at 0° C., warm to room temperature, and stir for 3 hours under N2. Quench the reaction with water and dilute with diethyl ether. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 0 to 5% methanol in CH2Cl2 gradient to afford 0.718 g (90%) of the titled product. Rf=0.29 (9/1 CH2Cl2/methanol). ES MS (m/z): 407 (M+).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH2:5][O:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[SH:18]CCO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]([O:6][CH2:5][CH:4]1[S:18][CH2:2][CH2:1][O:3]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COC(=O)c1ccccc1)OCC
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 5-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a Dean-Stark apparatus, and a glass stopper is added 2-(benzoyloxy)acetaldehyde diethyl acetal (0.469 mol, 111.85 g, 1.0 equiv.), 2-mercaptoethanol (0.516 mol, 40.34 g, 1.1 equiv.), para-toluenesulfonic acid monohydrate (0.047 mol, 8.92 g, 0.1 equiv.) and toluene (3.5 L). The reaction was heated to reflux and stirred while monitoring progress by TLC. When determined to be complete, the reaction was allowed to cool to ambient temperature before washing with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane as an oil (95.75 g, 90.9% yield). The crude product was advanced to the next reaction step without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[C:5]=3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[NH2:42][C:39]1[N:40]=[CH:41][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[C:12](=[O:27])[NH:13][C:14](=[O:26])[N:15]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)[C:5]=4[C:4]=3[N:3]=2)=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)c2c1cnc1ccc(Cl)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc3ncc4c(=O)[nH]c(=O)n(-c5cccc(C(F)(F)F)c5)c4c3n2)cn1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
9-chloro-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (400 mg, 1 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (440 mg, 2.0 mmol), potassium carbonate (414 mg, 3.0 mmol) and tetrakis(triphenylphosphine)palladium(58 mg, 0.05 mmol) were added to 40 mL dioxane and 2 mL water. The resulting mixture was reacted under reflux in the nitrogen protection for 18 hrs, cooled to room temperature, filtered with Celite, concentrated, and separated by silicagel column chromatography (EtOAc/PE=0-10/1) to obtain a crude product, which was washed with methanol to obtain a yellow solid of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)pyrimidino[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (56 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:24]=[O:25])=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O-:26]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:24]([OH:26])=[O:25])=[C:11]([CH:21]([CH3:22])[CH3:23])[N:12]2[CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: [O-][Cl+][O-]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ncco3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure D, ethyl3-formyl-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-6-carboxylate (Compound 38, 240 mg, 0.70 mmol) in t-BuOH (20 ml), 2-methyl-2-butene (2.0 ml) was added a solution of NaH2PO4 (1.69 g, 14.0 mmol) and NaClO2 (80%, 1.27 g, 14.0 mmol) in H2O (4 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→55% EtOAc-hexanes) to yield the title compound as a light tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(N(CC)CC)C.[C:16]([OH:20])(=[O:19])[CH:17]=[CH2:18].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:18][CH2:17][C:16]([OH:20])=[O:19]
Reactant: Fc1ccccc1S
Reactant: C=CC(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCSc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluorothiophenol (5.0 g, 39 mmol) was dissolved in tetrahydrofuran (50 ml) under a nitrogen atmosphere. Triethylamine (3.94 g, 5.33 ml, 85.8 mmol) was added. Acrylic acid (2.81 g, 2.67 ml, 39 mmol) was dissolved in tetrahydrofuran and added dropwise to the reaction solution over 2 h at room temperature. The mixture was stirred at room temperature overnight. 1M Hydrochloric acid (50 ml) was added and the phases were separated. The aqueous phase was washed with ethyl acetate (2×50 ml). The combined organic phases were dried over magnesium sulphate, filtered and concentrated under vacuum. A yellow oil was obtained which solidified upon storage at room temperature. The solid was triturated with hexane, filtered and dried under vacuum. The title compound was isolated as an off-white solid (4.19 g, 20.9 mmol, 54%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-cyanophenol and methyl bromoacetate in CH3CN was treated with K2CO3 and refluxed for 18 hours. Then the reaction was cooled to room temperature and concentrated. The residue was partitioned between EtOAc and H2O and the organic layer was washed with brine, driend (Na2SO4), filtered and evaporated. Flash chromatography (SiO2, hexanes/EtOAc) gave pure methyl 2-(4-cyanophenoxy)acetate.