Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[N:23]1[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:29][C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: O=Cc1ccncc1
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ccncc4)c23)c1

Procedure:
Analogously to Step 32.1, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenyl-amino)-1 H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 161 mg (1.5 mmol) of pyridine-4-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(pyrid-4-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 25 ml of DMEU with 8 ml (8 mmol) of DIBAL-H analogously to Example 32 and analogous working-up yield 4-(3-chlorophenylamino)-3-[(pyrid-4-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)7.7; FAB-MS: (M+H)+=352.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:7][CH:8]=1
Reactant: COc1ccc(C=CCCCCCC(=O)O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: COc1ccc(CCCCCCCC(=O)O)cc1
Yield: 95.9 %

Procedure:
This compound was synthesized from 8-(p-methoxyphenyl)-7-octenoic acid (1.24 g, 5 mmol) and Pd/BaSO4 (125 mg) by hydrogenation. Crystallization (petroleum ether) afforded the product (1.20 g, 96%) as white crystals (mp 42-43° C.). IR: 3400-2500, 1705 cm-1 ; 1H-NMR: 1.40 (m, 10H), 2.40 (m, 4H), 3.80 (s, 3H), 6.95 (q, 4H), 10.10 (bs, 1H). Anal. Calcd. for C15H22O2 : C, 71.97, H, 8.86%; Found: C, 72.07, H. 8.88%.
Reaction SMILES: [C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH2:23])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2].[Cl:26][CH:27]([Cl:31])[C:28](O)=[O:29]>>[C:1]([C:3](=[C:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][NH:23][C:28](=[O:29])[CH:27]([Cl:31])[Cl:26])[O:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH2:7][CH2:6]1)[CH3:4])#[N:2]
Reactant: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: O=C(O)C(Cl)Cl
Product: CC(C#N)=C1CCN(c2ccc(N3C[C@H](CNC(=O)C(Cl)Cl)OC3=O)cc2F)CC1
Yield: 63 %

Procedure:
The title compound was prepared by following the procedure of Example 29 and by using (S)-N-{3-[4-(4-(1-cyanoethylidene)-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-amine and dichloroacetic acid in 63% yield.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>ClCCl>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCBr
Solvent: ClCCl
Product: BrCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
3,4-Dihydro-2H-pyran (8.0 g, 95.36 mmol) was added to a 0° C. solution of 4-bromobutan-1-ol (12.0 g, 79.47 mmol) in dichloromethane (150 mL) followed by p-toulenesulphonic acid (20 mg). After 1 h, the reaction was carefully quenched with sat. aq. NaHCO3 solution (5 mL), washed with water (100 mL), brine (70 mL), and concentrated in vacuo. The residue was purified by SiO2 column chromatography using 2% EtOAc/hexanes as eluent to give 2-(4-bromobutoxy)tetrahydro-2H-pyran (16.57 g, 88%) as colorless oil. TLC: 10% EtOAc/hexanes, Rf≈0.50; 1H NMR (CDCl3, 300 MHz) δ 4.58 (t, J=2.5 Hz, 1H), 3.90-3.72 (m, 2H), 3.38-3.50 (m, 4H), 1.92-2.04 (m, 2H), 1.65-1.80 (m, 4H), 1.60-1.50 (m, 4H). Lit. ref: G. L. Kad; I. Kaur; M. Bhandari; J. Singh; J. Kaur Organic Process Research & Development 2003: 7, 339.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1.[Br-].[CH3:14][S+](C)C.[OH-].[K+].O>C(#N)C>[O:12]1[CH2:14][CH:11]1[C:9]1[O:10][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(C2OCCO2)o1
Reactant: C[S+](C)C
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: c1cc(C2OCCO2)oc1C1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
5-[1,3]Dioxolan-2-yl-furan-2-carbaldehyde (2.03 g, 12.1 mmol), trimethylsulfonium bromide (1.90 g, 12.1 mmol) and potassium hydroxide (779 mg, 13.9 mmol) were suspended in acetonitrile (75 mL), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane (2.25 g) was obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1.O1CCCC1>[Pd](Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH3:14])([CH3:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(C)(C)CC2=O
Agent: Cl[Pd]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OC(C)(C)C=C2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
A mixture of 2.1 g (10 millimoles) of 7-methoxy-2,2-dimethyl-4-chromanone, 50 ml of tetrahydrofuran, 20 ml of water, 2.66 g (15 millimoles) of palladium chloride and 4.2 g (0,11 mole) of sodium tetrahydro borate is stirred at 0° C. for 20 minutes and thereafter at 5° C. for a further 4 hours. The reaction mixture is filtered, the filtrate extracted twice with 50 ml of chloroform each. The solvent is distilled off, the residue taken up in 50 ml of toluene and distilled in the presence of anhydrous potassium hydrogen sulfate for 20 minutes. The reaction having been completed the organic phase is washed twice with 20 ml of water each and the solvent is removed. The crude product is purified by column chromatography. Thus 1.75 g of the desired compound are obtained in the form of a colorless oil, yield 85%.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(OC([NH:39][C:40]([CH3:45])([CH3:44])[C:41](O)=[O:42])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:39][C:40]([CH3:45])([CH3:44])[C:41]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:42]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)C(C)(C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 80.3 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 70 mg 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 71.3 mg of 352 after reverse phase HPLC purification. MS (Q1) 512.3 (M)+
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([NH2:11])=O)[CH2:3][CH2:2]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]#[N:11])[CH2:3][CH2:2]1
Reactant: NC(=O)c1snnc1C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1snnc1C1CC1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
4-Cyclopropyl-1,2,3-thiadiazole-5-carboxamide (4 g; 24 mmols) was dissolved in toluene (15 ml), and thionyl chloride (5 ml) was added thereto, followed by refluxing for 10 hours under heating. After cooling to room temperature, ice was added thereto to stop the reaction, and sodium hydrogen carbonate was added thereto to neutralize, followed by extracting with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to thereby obtain 2.1 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carbonitrile.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:11][CH2:10][C@H:9]([OH:12])[C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OC[C@H](O)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2ccc(C(F)(F)F)nc2)cc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of (R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethane-1,2-diol (6.4 g, 31 mmol) and pyridine (20 mL) in CH2Cl2 (200 mL) at 0° C. was added p-toluenesulfonyl chloride (7.0 g, 37 mmol) in small portions. The mixture was slowly warmed to rt and stirred for 40 hours, and then diluted with CH2Cl2 (100 mL). The organic phase was washed with aq. NaHCO3, brine, and dried (Na2SO4), and concentrated to yield the crude title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([C:9](=[O:26])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:37])=[CH:19][C:18]3=[O:24])=[CH:13][C:12]=2[F:25])[CH:7]1[C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(O)cc2=O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCOC(=O)C1C(C(=O)Nc2ccc(Cl)cc2)C1C(=O)Nc1ccc(-n2ccc(OC)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.5 %

Procedure:
A solution of 35 mg (0.07 mmol) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester (example 142, step 2) in 5 ml of acetone was treated with 94 mg (0.6 mmol) of potassium carbonate and 8 ul (0.08 mmol) of dimethylsulfate. The mixture was stirred 2 hrs at RT and filtered. Evaporation of the solvent and chromatography on silica gel with AcOEt/methanol 95:5 gave 5 mg (13%) of (1SR,2RS,3SR)-2-(4-chloro-phenylcarbamoyl)-3-[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-cyclopropanecarboxylic acid ethyl ester. Off-white solid. 526 (M−H)−.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[Cl:13][C:14]([Cl:25])([Cl:24])[CH:15]1[N:19]2[CH2:20][CH2:21][CH2:22][CH:18]2[C:17](=[O:23])[O:16]1.C(Br)C=C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([C:18]12[CH2:22][CH2:21][CH2:20][N:19]1[CH:15]([C:14]([Cl:13])([Cl:24])[Cl:25])[O:16][C:17]2=[O:23])[CH:1]=[CH2:2]
Reactant: CC(C)NC(C)C
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -68 °C
Reaction time: 0.67 h

Procedure:
To a solution of diisopropylamine (60 ml) in tetrahydrofuran (160 ml) was added dropwise n-butyllithium (2.64M hexane solution, 161 ml) over 20 minutes under ice-cooling, and the mixture was directly stirred for 40 minutes. To the mixture cooled to −68° C. was added dropwise a solution of 3-trichloromethyltetrahydropyrrolo[1,2-c]oxazol-1-one (80.0 g) in tetrahydrofuran (640 ml) over 30 minutes, and the mixture was directly stirred for 20 minutes. To the mixture was added allyl bromide (57 ml), and the mixture was directly stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution (1000 ml), and the mixture was extracted with ethyl acetate (800 ml). The separated organic layer was washed with water (800 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted with ethyl acetate (400 ml, 500 ml) twice. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the titled compound (86.1 g).
Reaction SMILES: ClC(Cl)C(O[CH2:6][C:7]1[CH2:8][S:9][C@@H:10]2[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:16](=[O:27])[N:11]2[C:12]=1[C:13]([OH:15])=[O:14])=O.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>CC(C)=O>[N:29]1([CH2:6][C:7]2[CH2:8][S:9][C@@H:10]3[C@H:17]([NH:18][C:19](=[O:26])[CH2:20][C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:27])[N:11]3[C:12]=2[C:13]([OH:15])=[O:14])[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)C(Cl)Cl)CS[C@H]12
Reactant: c1cn[nH]c1
Solvent: CC(C)=O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(Cn3cccn3)CS[C@H]12

Procedure:
3-Dichloroacetoxymethyl-7β-(2'-thienylacetamido)ceph-3-em-4-carboxylic acid (3.2 g., 6.9 mmole.) was dissolved in 50%-aqueous acetone (60 ml.). and treated with pyrazole (1.6 g., 24 mmole.), and the solution heated at 50° for 35 minutes. The acetone was removed under reduced pressure, and the aqueous residue was extracted with ether (9 × 20 ml.). After drying, the ether was evaporated and the solid residue recrystallised from aqueous alcohol (1.3 g., 47%), mp. 180°-185° (decomp) [α]D30 = 53.5° (c 1.01, ethanol), λmax (ethanol) 236 nm. (β 14,000), 261 nm. (ε = 8,250) (shoulder), νmax (Nujol) 3272 (--NH), 1773 (β-lactam), 1712 (--COOH), 1660 and 1532 cm-1 (--CONH--). (Found: C, 50.9; H, 4.2; N, 13.9; S, 15.7. C17H16N4S2O4 requires C, 50.5; H, 4.0; N, 13.9; S, 15.9%). N.M.R. (D2O, with NaHCO3) 2.30, 3.62, 2.41τ (-N-CH=CH-CH=N), Rf 0.37 (Systems B), 0.12 (System C).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][NH2:8])[CH:2]=1.CO[CH:12]=[CH:13][C:14]#[N:15].[O-]CC.[Na+]>C(O)C>[C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:12]=[CH:13][C:14]([NH2:15])=[N:8]2)[CH:2]=1
Reactant: COC=CC#N
Reactant: Cc1cccc(NN)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(-n2ccc(N)n2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
m-Tolylhydrazine (200 mg, 1.64 mmol), 3-methoxyacrylonitrile (0.137 mL, 1.64 mmol), and sodium ethoxide (111 mg, 1.64 mmol) were dissolved in ethanol (8 mL) and stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate/hexanes, linear gradient) to afford 1-m-tolyl-1H-pyrazol-3-amine. MS ESI calc'd. for C10H12N3 [M+H]+ 174. found 174. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.46 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 5.69 (d, J=2.5 Hz, 1H), 5.01 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1)[CH:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18]
Reactant: O=C(Cl)c1cccnc1
Reactant: COc1ccccc1-c1c[nH]c2ccc(F)cc12
Product: COc1ccccc1-c1cn(C(=O)c2cccnc2)c2ccc(F)cc12
Yield: 66 %

Procedure:
By following the procedure of Example 1 substantially faithfully while using 10.0 g of 5-fluoro-3-(2-methoxyphenyl)indole in the place of 3-phenylindole and using nicotinoyl chloride in the place of benzoyl chloride, 9.5 g of 5-fluoro-3-(2-methoxyphenyl)-1-nicotinoylindole (66.0%) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1[CH:24]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 588 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (243 mg, 6.39 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted ethyl acetate (3×50 mL). The product precipitated out of the organic phase to give 535 mg (51%) of the title compound as a red solid, mp 124–128° C. 1H-NMR (300 MHz, DMSO-d6) 8.16 (d, 2H, J=8.7), 8.02 (d, 1H, J=15.9 Hz), 7.95 (m, 3H), 7.70 (t, 1H, J=7.80 Hz), 7.61 (d, 1H, J=16.2 Hz), 7.18 (d, 1H, J=8.70 Hz), 7.15 (s, 1H), 6.83 (t, 1H, J=6.0 Hz), 6.66 (s, 1H), 3.84 (s, 6H), 3.13 (m, 4H), 1.18 (m, 4H). HRMS (ESI) Calcd. for C26H27N3O5S: 494.1750 [(M+H)+]; Found: 494.1750.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6]O.CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][Br:35]
Reactant: BrC(Br)(Br)Br
Reactant: COC(CCCO)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCCBr)OC

Procedure:
A solution of 0.1 moles of 4,4-dimethoxybutanol in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is allowed to react for 18 hours with 0.1 moles of carbon tetrabromide. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated to a crude product which is purified by distillation to yield 4,4-dimethoxybutylbromide. This bromide is then converted into the diethyl phosphonate using the procedure described in Example 2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[N:20][CH:21]=[CH:22][C:10]=3[NH:9][C:8]2=[O:23])[CH2:3][CH2:2]1.Cl.C(O)C.[S:28]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29]1.C([BH3-])#N.[Na+]>CO>[S:28]1[CH:32]=[CH:31][C:30]([CH2:33][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]4[CH:19]=[N:20][CH:21]=[CH:22][C:10]=4[NH:9][C:8]3=[O:23])[CH2:5][CH2:6]2)=[CH:29]1
Reactant: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCNCC1
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C1Nc2ccncc2C(c2ccccc2)N1C1CCN(Cc2ccsc2)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
To a solution of 500 mg (1.62 mmol) of 3-(piperidin-4-yl)-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[4,3-d]pyrimidine in 30 mL of methanol were added 1,200 mg of 10% HCl/ethanol solution, 727 mg (6.48 mmol) of 3-thiophenecarboxaldehyde and 407 mg (6.48 mmol) of sodium cyanoborohydride under ice-cooling, and the mixture was stirred for 10 hours at ambient temperature. Then, the reaction mixture was concentrated in vacuo, and water was added to the residue. The mixture was adjusted to pH 10 and extracted with chloroform. The organic layer separated was dried on potassium carbonate, and then concentrated in vacuo. The residue was purified by means of column chromatography (silica gel, 1:9 methanol:chloroform) to give 550 mg (1.36 mmol) of the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([S:13][CH2:14][CH2:15][OH:16])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[Cl:18][CH:19]([CH2:23][Cl:24])[C:20](O)=[O:21]>C1CCCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:18][CH:19]([CH2:23][Cl:24])[C:20]([O:16][CH2:15][CH2:14][S:13][C:2]([F:1])([F:17])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6])=[O:21]
Reactant: O=C(O)C(Cl)CCl
Reactant: OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: O=C(OCCSC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(Cl)CCl
Yield: 96.5 %

Procedure:
1,1,1,2,2,3,3,4,4-nonafluoro-4-iodobutane (138.4 g (400 mmol)) was dissolved in a mixture liquid of DMF (400 ml) and water (80 ml), and mercaptoethanol (32.2 g (400 mmol)) was added. Further, sodium formate (27.2 g (400 mol)), sodium sulfite heptahydrate (100.9 g (400 mmol)) were added, and stirred at room temperature (23° C.) for one night. Water (1 L) and isopropyl ether (1 L) were added to the reaction liquid, which was separated. A water layer was further extracted with isopropyl ether (500 ml×2). The organic layer was washed with 10% hydrochloric acid (500 ml), water (500 ml) and a saturated saline solution (500 ml), dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 2-(perfluorobutylthio)ethanol. Then, p-toluene sulfonic acid monohydrate (2.5 g (13.1 mmol)) was added to a solution of 2-(perfluorobutylthio)ethanol (50 g (equivalent to 158 mmol)) and 2,3-dichloropropionic acid (22.5 g (157 mmol)) in cyclohexane (500 ml), and was subjected to dehydration condensation reaction (bath temperature: 90° C.) for one night by using a Dean-Stark method. The reaction liquid was filtered with celite. An organic layer was washed with water three times and with saturated saline solution, and dried over anhydrous magnesium sulfate. The filtration and concentration under reduced pressure gave crude 2-(perfluorobutylthio)ethyl 2,3-dichloropropionate (63.8 g). Yield: 96.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2)([O-])=O.CS(C)=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[N:7]2
Reactant: O=[N+]([O-])c1ccc2nccnc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CS(C)=O
Product: Nc1ccc2nccnc2c1
Yield: 90 %

Procedure:
6-Nitro-quinoxaline (3, 5 mmol) was hydrogenated in the presence of 5% Pd/C (50 mg) under at room temperature in ethanol (30 ml) for 6-10 h. After the reaction 2 ml DMSO was added to the mixture and filtered. The filtrate was poured into water (200 ml) and the precipitate was filtered to give 6-amino-quinoxaline (4a-d) (90-95%).
Reaction SMILES: [N:1]([C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O=S(Cl)Cl>[N:1]([C:4]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: Nc1ccccc1
Reactant: [N-]=[N+]=Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1c(C(=O)Nc2ccccc2)cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Azido-3-trifluoromethyl-benzoic acid (460 mg, 2 mmol, compound IX) was dissolved in 2 ml of SOCl2 and the reaction mixture was heated at 80° C. for 1 hour. The remaining SOCl2 was evaporated in vacuo and the residue was coevaporated with dry benzene. Dry CH2Cl2 (2 ml) was added followed by a dropwise addition of 200 μl of aniline (2 mmol). The reaction mixture was stirred at room temperature for 1 hour. Saturated aq. NaHCO3 was added and the product was extracted with CH2Cl2. The resulting amide was purified by recrystallization from methanol. The yleld was 521 mg (86%).