Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH2:47][CH2:46][C:45]4[N:44]5[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]5)=[CH:38][C:37]=4[C:36]3=[O:48])[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[CH2:47][CH2:46][C:45]3[N:44]4[C:39]([CH2:40][CH2:41][CH2:42][CH2:43]4)=[CH:38][C:37]=3[C:36]2=[O:48])=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCc5c(cc6n5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A mixture of 149a (97 mg, 0.15 mmol), NaBH4 (17 mg, 0.45), and methanol (10 mL) was stirred at 25° C. for 1 h. The reaction mixture was then quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 149 (62 mg, 63%). MS-ESI: [M+H]+ 651.3. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.46 (d, J=5.0 Hz, 1H), 8.43 (s, 1H), 7.83 (d, J=3.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.38-7.36 (m, 1H), 7.31 (J=5.0 Hz, 1H), 7.25-7.23 (m, 1H), 6.04 (s, 1H), 4.57-4.55 (m, 2H), 4.48-4.46 (m, 1H), 4.42-4.38 (m, 2H), 4.35-4.33 (m, 1H), 4.15-4.12 (m, 1H), 3.96-3.94 (m, 1H), 3.82-3.78 (m, 2H), 3.69-3.67 (m, 1H), 3.59 (s, 3H), 3.41-3.38 (m, 2H), 3.18-3.15 (m, 2H), 3.00-2.95 (m, 3H), 2.73-2.71 (m, 2H), 2.30-2.28 (m, 2H), 2.20-2.16 (m, 1H), 1.93-1.89 (m, 3H), 1.77-1.75 (m, 1H), 0.93 (d, J=6.5 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)=[CH:5][CH:4]=1.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH:21]=2)=[CH:7][CH:8]=1
Reactant: ClCCCN1CCCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(O)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2-c2cccc(OCCCN3CCCCC3)c2)cc1
Yield: 66.8 %

Procedure:
A manner similar to that used in Example 1, 3.09 g (8 mmol) of 2-(4-Methoxyphenyl)-3-(3-hydroxyphenyl)-6-methoxybenzo[b]thiophene, 2.4 g (12 mmol) of 1-(3-chloropropyl)piperidine hydrochloride, 5.5 g (40 mmol) of K2CO3 in 200 mL of DMF was coverted to 2.8 g of the title compound, isolated as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:12]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of 4-methyl-2-nitro-phenylamine (202 mg, 1.33 mmol) and benzaldehyde (0.68 mL, 6.65 mmol) in 5 mL dry dichloromethane at room temperature, was added sodium triacetoxyborohydride (282 mg, 1.33 mmol). Then acetic acid (76 μl, 1.33 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the solvent was removed in vacuo. The crude material was purified by flash chromatography to yield 300 mg (1.24 mmol, 94%) of benzyl-(4-methyl-2-nitro-phenyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1.CCN(S(F)(F)[F:21])CC>ClCCl>[Cl:1][C:2]1[C:7]([C:8]2([F:21])[CH2:11][O:10][CH2:9]2)=[CH:6][N:5]=[C:4]([C:13]#[N:14])[CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: N#Cc1cc(Cl)c(C2(O)COC2)cn1
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(C2(F)COC2)cn1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
To a solution of 4-chloro-5-(3-hydroxyoxetan-3-yl)pyridine-2-carbonitrile (example 123b, 2.0 g, 9.5 mmol) in dry dichloromethane (50 ml) under an argon atmosphere cooled down to −75° C. was added DAST (1.61 g, 1.32 ml, 9.97 mmol). The reaction was stirred at −75° C. for 15 min, then let to warm up to 0° C. and stirred at 0° C. for 1 hour. The reaction was then quenched by addition of a 2M aqueous solution of sodium carbonate. The bi-phasic mixture was stirred at room temperature for 15 minutes, poured into a separatory funnel and extraction was carried out. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (1.81 g, 90%). MS (ESI, m/z): 213.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1ccccc1C(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 94.2 %

Procedure:
Beginning with 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.0 μL (0.0458 mMol) 2-methylbenzoyl chloride, 14.3 mg (95%) of the title compound were recovered.
Reaction SMILES: [C:1]([C:3](=[CH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1)[C:4](OCC)=[O:5])#[N:2].[NH:19]1C(C2C(=O)N3C=CC=CC3=NC=2)=N[N:21]=[N:20]1>>[CH2:17]([C:14]1[CH:15]=[CH:16][C:11]2[N:12]([CH:13]=1)[C:4](=[O:5])[C:3]([C:1]1[NH:2][N:21]=[N:20][N:19]=1)=[CH:9][N:10]=2)[CH3:18]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: CCOC(=O)C(C#N)=CNc1ccc(CC)cn1
Product: CCc1ccc2ncc(-c3nnn[nH]3)c(=O)n2c1
Yield: 28 %

Procedure:
The title compound (28% yield, m.p. 289°-290.5° with decomposition) was prepared from ethyl 2-cyano-3-(5-ethyl-2-pyridylamino)acrylate in a manner similar to that described for the preparation of 3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one in Example 2.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1>[CH:1]1([O:7][N:8]2[C:13]([CH3:14])([CH3:15])[CH2:12][CH:11]([NH:16][C:17]([C:18]([NH:28][CH2:27][CH2:25][OH:26])=[O:19])=[O:22])[CH2:10][C:9]2([CH3:24])[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=O)NC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: NCCO
Solvent: Cc1ccccc1
Product: CC1(C)CC(NC(=O)C(=O)NCCO)CC(C)(C)N1OC1CCCCC1
Yield: 63.9 %

Procedure:
A mixture of 9.1 grams (26.7 mmol) of methyl N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxamate, 1,8 grams (29.4 mmol) of ethanolamine and 35 ml of toluene is heated at reflux for 30 minutes. Methanol is removed from the reaction mixture by fractional distillation. The reaction mixture is poured into ethyl acetate (125 ml) to afford 6.3 grams (64% yield) of the title compound as a white solid melting at 190°-192° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[C:5]2[C:20]([CH3:27])=[C:21]([OH:26])[C:22]([CH3:25])=[C:23]([CH3:24])[C:4]=2[O:3]1.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][O:26][C:21]2[C:22]([CH3:25])=[C:23]([CH3:24])[C:4]3[O:3][C:2]([CH3:28])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]5)=[CH:11][CH:12]=4)[C:5]=3[C:20]=2[CH3:27])=[CH:33][CH:32]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(N3CCN(C)CC3)cc1)C(C)(C)O2
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(N4CCN(C)CC4)cc2)C(C)(C)O3)cc1
Yield: 42 %

Procedure:
Using 2,2,4,6,7-pentamethyl-3-[4-(4-methyl-1-piperazinyl)phenyl]-2,3-dihydrobenzofuran-5-ol and 4-methoxybenzyl chloride, the title compound was obtained in the same manner as In Example 1.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[C:16]([F:28])[CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[O:33])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile (1.6 g), 2-bromo-1-(4-methoxyphenyl)ethanone (1.1 g) and N,N-dimethylformamide (19 mL) was added 60% sodium hydride (0.23 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.8 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:22][NH2:23]>CC(O)C.O>[Br:1][C:2]1[CH:9]=[C:6]2[CH:7]=[N:23][NH:22][C:5]2=[N:4][CH:3]=1
Reactant: NN
Reactant: O=Cc1cc(Br)cnc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: Brc1cnc2[nH]ncc2c1
Temperature: 145 °C

Procedure:
A mixture of 5-bromo-2-fluoronicotinaldehyde (0.580 g, 2.8 mmol), 4-methylbenzenesulfonic acid (0.060 g, 0.35 mmol) and anhydrous hydrazine (0.450 ml, 14 mmol) in 5 mL of i-PrOH was heated at 145° C. for 15 min in the microwave (Initiator by Biotage). The reaction was diluted with H2O and the solid was filtered washed with H2O and air-dried to give a white amorphous solid. MS (M+H)+ 198, 200.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:6]=[CH:7][C:8](=[O:12])[C:9]=1[O:10][CH3:11])=[O:5].[Cl:13][C:14](=[CH2:19])[CH:15]=[CH:16]OC>C1C=CC=CC=1>[CH3:11][O:10][C:9]1[C:8](=[O:12])[C:7]2[C:6]([C:4](=[O:5])[C:3]=1[O:2][CH3:1])=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2
Reactant: COC1=C(OC)C(=O)C=CC1=O
Reactant: C=C(Cl)C=COC
Solvent: c1ccccc1
Product: COC1=C(OC)C(=O)c2cc(Cl)ccc2C1=O

Procedure:
A benzene (8 ml) solution of 2,3-dimethoxybenzo-1,4-quinone (1.0 g, 5.9 mmol) and 3-chloro-1-methoxy-1,3-butadiene (1.4 g, 12.0 mmol) is stirred for 35 hours under an inert atmosphere. After this time, oxygen or air is briefly bubbled through the solution (20 minutes) and the contents are passed through a silica gel plug to afford 1.07 g (72%) of analytically pure 2,3-dimethoxy-6-chloro-1,4-naphthoquinone, mp 127°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.[N:14]1([CH2:20][C:21]2[CH:22]=[C:23]3[C:32]4[N:31]([CH:33]=2)[C:30](=[O:34])[C:29]([C:35](OCC)=[O:36])=[CH:28][C:27]=4[CH2:26][CH2:25][CH2:24]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:35]([C:29]2[C:30](=[O:34])[N:31]3[CH:33]=[C:21]([CH2:20][N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH:22]=[C:23]4[CH2:24][CH2:25][CH2:26][C:27]([CH:28]=2)=[C:32]34)=[O:36])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Agent: C[Al](C)C
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cc2c3c(cc(CN4CCOCC4)cn3c1=O)CCC2
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 4-chlorobenzylamine (142 mg, delivered as a 1M methylene chloride solution) in anhydrous CH2Cl2 (3 mL), is added trimethylaluminum (482 μL, 2 M solution in heptane). After two hours at room temperature, ethyl 6-(morpholin-4-ylmethyl)-3-oxo-9,10-dihydro-3H,8H-pyrido[3,2,1-ij]quinoline-2-carboxylate (Preparation 18, 327 mg) is added as a solid in one portion. Stirring is continued for 2.5 hours before quenching with 10 mL of a 35% aqueous solution of Rochelle's salt. This biphasic, gelatinous mixture is stirred for two hours before separating the layers and extracting the aqueous layer five times with CH2Cl2. The resulting solution is concentrated in vacuo to give a bright yellow solid which is recrystallized from acetone (reflux, 62 mL/g) to afford 251 mg (73%) of the title compound as a canary yellow solid. Physical characteristics: M.p. 200-201° C.; 1H NMR (CDCl3); δ10.2, 9.07, 8.54, 7.41, 7.33, 7.28, 4.67, 3.71, 3.53, 3.02, 2.48, 2.02; 13C NMR (CDCl3): δ165.5, 157.5, 140.6, 138.6, 137.7, 134.7, 132.7, 130.9, 129.0, 128.6, 127.1, 125.2, 113.1, 109.2, 66.8, 60.4, 53.6, 42.9, 30.4, 28.7, 21.3; HRMS m/z 452.1747 (C25H26ClN3O3+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][S:12][CH3:13])[C:3]=1[NH2:14].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:3]=1[N:14]=[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15])[N:9]2[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCCNc1nc(C)nc(Cl)c1N
Reactant: O=Cc1ccccc1Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CSCCn1c(-c2ccccc2Cl)nc2c(Cl)nc(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Heat a mixture of 6-chloro-2-methyl-N4-(2-methylsulfanylethyl)pyrimidine-4,5-diamine (1.63 g, 0.007 mol), 2-chlorobenzaldehyde (1.96 g, 0.014 mol), and 15% FeCl3 on SiO2 (4.89 g) in 1,4-dioxane (15 mL) to 100° C. for 16 h. Cool the reaction and remove the silica by filtration through diatomaceous earth. Concentrate the filtrate under reduced pressure to give a residue. Dissolve the residue in dry dichloromethane (10 mL) and add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.58 g, 0.007 mol) at 0° C. Stir the reaction mixture at room temperature for 2 h. Dilute the reaction mixture with dichloromethane, and wash with 1 N aqueous sodium hydroxide solution, water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give a residue. Purify the residue on a silica gel column eluting with ethyl acetate:hexane (15:85) to give the title compound (1.9 g). ES/MS m/z 353 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[O:14])[N:7]2[CH:15]=[N:16][N:17]=[C:6]12)[CH2:2][CH2:3][CH3:4].[Br:18]N1C(=O)CCC1=O>C1COCC1>[Br:18][C:11]1[NH:10][C:9]2[C:8](=[O:14])[N:7]3[CH:15]=[N:16][N:17]=[C:6]3[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:13]=2[N:12]=1
Reactant: CCCCn1c2nc[nH]c2c(=O)n2cnnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCn1c2nc(Br)[nH]c2c(=O)n2cnnc12
Temperature: 70 °C
Yield: 5.5 %

Procedure:
To a mixture of 9-butyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (65 mg, 0.28 mmol) in THF (2 mL) was added N-bromosuccinimide (49.8 mg, 0.280 mmol). The mixture was heated in a microwave reactor at 70° C. for 10 minutes. The mixture was purified with prep LCMS to give the desired product (4.8 mg, 6%). LCMS calculated for C10H12BrN6O (M+H): 311.0. Found: 311.0, 313.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].I[CH3:14].Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: CI
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1ccc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
980 mg (5.0 mmol) of 5-bromoindole were added to a solution of 420 mg (7.5 mmol) of pulverized KOH in dimethyl sulfoxide (15 ml) following stirring 15 min at RT. After stirring at RT a further 5 min, 342 μl (5.5 mmol) of iodomethane were added and the mixture was then stirred at RT over a period of 1 h. Following neutralization with 5% strength aq. hydrochloric acid, the reaction mixture was extracted with EA. The organic phase was successively washed with water and a satd aq. NaCl soln and dried over MgSO4. Following filtration and removal of the solvent in vacuo there were obtained 980 mg (4.7 mmol, 93%) of 5-bromo-1-methylindole.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1>>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[S:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][C:10]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCSc2ccc(N)cc2C1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CN(CCOC)CCS3)ncc1Cl
Yield: 41.5 %

Procedure:
Following the procedure of 512f, 8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00029 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.086 g, 0.00029 mol) were reacted. Purification was carried by SiO2 prep plate chromatography giving 2-{5-chloro-2-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide (0.06 g, 43%) as a grey solid. MP: 176-7° C.; 1H-NMR (DMSO-d6) 11.63 (s, 1H), 9.53 (s, 1H), 8.75 (d, 1H), 8.72 (d, 1H), 8.24 (s, 1H), 7.75-7 (d, 1H), 7.61 (s, 1H), 7.51-7 (m, 2H), 7.36-8 (d, 1H), 7.16-8 (t, 1H), 7.11-4 (d, 1H), 5.17 (s, 1H), 3.98 (s, 2H), 3.89 (s, 1H0, 2.80-1 (d, 2H), 2.67 (d, 2H); LC/MS (ESI+): 499 (M).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([CH3:11])[C:7]([F:10])([F:9])[F:8])C.O.[NH2:14][NH2:15]>C(O)C>[CH3:11][C:6]1([C:7]([F:10])([F:9])[F:8])[NH:15][NH:14][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)C=C(C)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1(C(F)(F)F)CC(=O)NN1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(300 mg, 1.65 mmol) 4,4,4-Trifluoro-3-methyl-but-2-enoic acid ethyl ester (CAS 24490-03-7) was dissolved in ethanol (3 ml) and hydrazine monohydrate 64% in ethanol (0.13 ml, 1.73 mmol, 1.05 equiv.) was added at room temperature and stirred in a sealed tube for 16 hours at 80° C. The reaction mixture was evaporated to dryness. The desired (RS)-5-methyl-5-trifluoromethyl-pyrazolidin-3-one (280 mg, quant.) was obtained as a white solid, MS: m/e=169.2 (M+H+).
Reaction SMILES: [C:1]([S:14](F)(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[CH2:18]([NH2:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>O>[C:1]([S:14]([NH:24][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCN
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 65 °C
Yield: 81.3 %

Procedure:
A 2-liter flask fitted with a thermocouple, overhead stirrer, dropping funnel and heating mantle was charged with C4F9SO2F (543 g, 1.80 mole). To this stirred material was slowly added a mixture of hexylamine (194.0 g, 1.90 mole) and triethylamine (194.0 g, 1.90 mole); the ensuing mixture was stirred and heated at 65° C. for 2 hours. Water (555.0 g) was then added, and stirred for an additional 30 minutes. The lower phase was separated, put into a flask and heated to 60° C. To this heated mixture was added sulfuric acid (50 g concentrated sulfuric and 500 g water). The lower phase of the resulting two-phase mixture was then separated, washed with water (500 g), and placed in a flask with a one-plate distillation head. The flask was heated to 80° C. at 20-25 mm Hg (2.7-3.3 kPa) and the distillate collected over a period of one hour. The material that remained in the flask was further distilled at 8 mm Hg (0.4 kPa) and a pot temperature of 138-143° C., yielding C4F9SO2NH(CH2)5CH3 (561.0 g). NMR and GC/MS analyses were consistent with the indicated material.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([OH:29])[C@@H:16]([S:18][C:19]3[C:24](OCOC)=[CH:23][CH:22]=[CH:21][N:20]=3)[CH3:17])=[CH:11][CH:10]=2)=CC=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[CH3:17][C@H:16]1[C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[O:29][C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[S:18]1
Reactant: COCOc1cccnc1S[C@@H](C)C(O)c1ccc(OCc2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1Sc2ncccc2O[C@H]1c1ccc(O)cc1
Reaction time: 0.25 h

Procedure:
The compound synthesized in the above (6) was mixed with anisole (8.52 mL, 78.8 mmol) and trifluoroacetic acid (20 mL, 0.26 mol) under cooling with ice, and stirred for 15 minutes under cooling with ice. Aqueous saturated sodium hydrogencarbonate solution was added, then the reaction solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, water and saturated saline in that order, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash column chromatography (hexane/ethyl acetate=1/1), and further recrystallized (ethyl acetate/n-heptane) to obtain the entitled compound (1.9 g, 35% in 2 steps) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](O)=[O:22])[N:4]=1)#[N:2].C(N1CCOCC1)C.[NH2:32][C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:32][C:33]([CH3:41])([CH3:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)CCC(C)(C)N
Reactant: N#Cc1nc(C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)CCC(C)(C)NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylic acid (47 mg, 0.15 mmol), N-ethylmorpholine (27 μL, 0.21 mmol), methyl 4-amino-4-methylpentanoate (crude as its acetic acid salt, 41 mg, 0.20 mmol), DCC (41 mg, 0.20 mmol) and HOBT (56 mg, 0.41 mmol) were suspended in CH2Cl2 (1 mL). The resulting mixture was stirred at room temperature for 20 hours. The reaction crude was filtered through a pad of celite and the filtrate was washed with sat'd NaHCO3 solution and H2O. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-40% EtOAc/hexanes) to give the title compound in 12 mg. MS: (−) m/z 432.22 (M−1).