Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=2)[NH:15][C:14]([C:21]([F:24])([F:23])[F:22])=[C:13]3[C:25]([O:27][CH3:28])=[O:26])[CH:10]([CH2:29][Cl:30])[CH2:9]1)=O)(C)(C)C.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][C:37](C(O)=O)=[CH:36]2>>[Cl:30][CH2:29][CH:10]1[C:11]2=[C:12]3[C:16](=[C:17]([OH:20])[CH:18]=[C:19]2[N:8]([C:6]([C:37]2[NH:38][C:39]4[C:35]([CH:36]=2)=[CH:34][C:33]([O:32][CH3:31])=[CH:41][CH:40]=4)=[O:5])[CH2:9]1)[NH:15][C:14]([C:21]([F:22])([F:24])[F:23])=[C:13]3[C:25]([O:27][CH3:28])=[O:26]
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(O)cc3c(c12)C(CCl)CN3C(=O)c1cc2cc(OC)ccc2[nH]1

Procedure:
Methyl 1-chloromethyl-5-hydroxy-3-(5-methoxy-1H-indol-2-ylcarbonyl)-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate was prepared in the same manner as above by using 11.2 mg (25 μmol) of methyl 3-t-butoxycarbonyl-1-chloromethyl-5-hydroxy-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate and 4.8 mg (25 μmol) of 5-methoxyindole-2-carboxylic acid in a yield of 7.2 mg (55%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1.CO.[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(O)c(N)c1

Procedure:
Methyl-2-(4-hydroxy-3-nitrophenyl)acetate (2.31 g, 10.9 mmol) was dissolved in THF (20 mL) and MeOH (20 mL) and 10% palladium on carbon (210 mg) was added slowly at RT. The reaction mixture was hydrogenated for 2 h at 39 psi hydrogen pressure, filtered through Celite and washed with MeOH. The solvent was removed under a vacuum and the residue purified by means of column chromatography (n-hexane/EA=2:1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][N+:27]2([O-:42])[CH2:28][CH:29]([C:31]([OH:33])=[O:32])[CH2:30]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2
Reactant: O=C(O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)C1C[N+]([O-])(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Reaction time: 0.17 h

Procedure:
A slurry of 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-phenyl)methyl)azetidine-3-carboxylic acid (0.084 g, 0.18 mmol) and mCPBA (0.063 g, 0.37 mmol) in 5 mL 10% MeOH/DCM was stirred rapidly at ambient temperature. After about 10 min, the reaction mixture became clear. After 10 additional minutes precipitates formed. After 10 additional minutes, the reaction mixture was filtered, rinsing with DCM. The solid was collected and dried in vacuo to give 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)azetidine-3-carboxylic acid N-oxide as a mixture of isomers. The isomers were separated by RPHPLC (A=0.2% formic acid in water; B=0.04% formic acid in acetonitirle; 30×100, Gemini Axia, Sum) to give (1r,3s)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide and (1s,3r)-3-carboxy-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidine 1-oxide. MS (ESI) m/z: Calculated: 475.1; Observed: 476.1 (M++1).
Reaction SMILES: [H-].[Li+].[CH2:3]=[O:4].CO.Cl[CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[CH2:13]([C:8]1([O:4][CH2:3]1)[C:9]([O:11][CH3:12])=[O:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCC(Cl)C(=O)OC
Reactant: C=O
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCC1(C(=O)OC)CO1
Reaction time: 1 h

Procedure:
Lithium hydride (0.32 g, 0.040 m), paraformaldehyde (0.16 g, 0.0053 m), and methanol (0.32 g, 0.010 m) were heated together in 25 ml DMF at 30°-40° C. After 1 hour, methyl α-chloropalmitate (3.05 g, 0.010 m) was added; the remaining paraformaldehyde (0.16 g, 0.0053 m) was added in two portions. The reaction was worked up after 51/2 hours of heating. The reaction mixture was extracted with hexane; the hexane was washed with water and dried over Na2SO4. The mixture was filtered and stripped to a crystalline residue. The residue was recrystallized from methanol to give 2.49 g (83.5%) yield of methyl tetradecylglycidate (m.p. 47°-48° C., glc purity>99%).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:10]3[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=3[CH:21]=2)[S:4][N:3]=1.C(N(CC)CC)C.Cl.[CH2:36]([C:38]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)C>CN(C=O)C>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[S:14][C:10]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:8][C:7]([C:5]3[S:4][N:3]=[C:2]([N:41]4[CH2:42][CH2:43][C:38]([CH3:36])([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39][CH2:40]4)[N:6]=3)=[CH:21][C:11]=2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1(CC)CCNCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3nc(N4CCC(C)(C(=O)OCC)CC4)ns3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea (100 mg, 0.24 mmol) and Triethylamine (73 mg, 0.72 mmol) in DMF (10 mL) was added ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (100 mg, 0.48 mmol) and the mixture stirred at rt for 1 h giving a suspension. LCMS showed only SM so the reaction was heated at 90° C. for 3 days after which time LCMS showed a major product peak. The reaction mixture was concentrated in vacuo to give an orange gum, which was purified by flash column chromatography (Biotage SP4, 12 g 2-10% MeOH/DCM)) to give the desired product as a cream solid (100 mg, 52%) MS: 552.11 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O>CN(C=O)C>[CH:1]1([N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[CH:11]=3)[C:6]([C:14]#[N:15])=[C:5]2[C:16]2[CH:17]=[CH:18][C:19]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][CH:21]=2)[CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: CC(C)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CC2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A mixture of (1-cyclopropyl-6-hydroxy-2-(4-isopropylamino-phenyl)-1H-indole-3-carbonitrile (0.099 g, 0.3 mmol), Cs2CO3 (0.244 g, 0.75 mmol), 2-chloropyrimidine (0.069 g, 0.6 mmol) in DMF (2.0 mL) was stirred at 70° C. overnight. After cooling to room temperature the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide 1-cyclopropyl-2-(4-isopropylamino-phenyl)-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile as a solid (0.104 g, 85%).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[NH:33][CH2:34][CH2:35][NH:36]C(OC(C)(C)C)=O>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:31])([CH3:32])[CH3:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:10]=1[NH:33][CH2:34][CH2:35][NH2:36]
Reactant: CC(C)(C)OC(=O)NCCNc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](Oc1ccc(Br)c(NCCN)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid is added to a solution of product from Step A in methylene chloride. After one hour at room temperature, the solution is evaporated, and the residue is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase is washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([NH2:14])=[CH:12][CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27](Cl)=[O:28])=[C:20]2[N:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([NH:14][C:13]3[N:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[N:10]=[CH:11][CH:12]=3)=[O:28])=[C:20]2[N:19]=1
Reactant: Nc1ccnn1-c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccnn1-c1cccc(C(F)(F)F)c1)c1cnn2ccc(Cl)nc12
Temperature: 50 °C
Yield: 58.7 %

Procedure:
To a stirred solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (200 mg, 0.88 mmol) in dichloromethane (30 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (215 mg, 1.0 mmol) and diisopropylethylamine (130 mg, 1.0 mmol). The mixture was heated to 50° C. overnight. After cooling to room temperature, the mixture was concentrated to afford crude 5-chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, yield 58%), which was used for the next step without further purification. MS (ESI) m/z: 407.2
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=O)[CH2:11][CH2:10]1.Cl>C(O)C>[CH:12](=[C:11]1[C:1](=[O:8])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:9][CH2:10]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCOc2ccccc21
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)COc2ccccc21

Procedure:
(66) To a solution of benzaldehyde (430 mg, 4.05 mmol) and 4-chromanone (500 mg, 3.37 mmol) in 8.4 ml of ethanol heated almost to boiling was added 1.7 ml of concentrated hydrochloric acid dropwise. After refluxing for 2 days, the solution was cooled overnight, and a precipitate formed. The precipitate was recrystallized from ethanol to afford 367 mg (46.1%) of white flakes: mp 111.8-113.4° C. (lit. mp 112° C., Powell, J. Am. Chem. Soc., 1923, 45, 2708-2711). 1H NMR (250 MHz) δ 8.06-8.02 (dd, 1H), 7.90 (s, 1 H), 7.54-7.31 (m, 6 H), 7.09 (t, 1 H), 7.00-6.96 (d, 1 H), 5.37 (s, 2 H); 13C NMR (62.7 MHz) 182.4, 161.3, 137.7, 136.1, 134.6, 131.1, 130.2, 129.7, 128.9, 128.1, 122.1, 118.1, 67.8 ppm.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.2 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 0.018 mol), K2CO3 (5.5 g, 0.04 mol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 0.018 mol), and dimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: [F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[OH:14]OS([O-])=O.[K+]>CO.O>[F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:9][C:8]([S:10]([CH3:11])=[O:14])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(F)c(F)cc2s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)c1nc2cc(F)c(F)cc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 240 mg (1.1 mmol) 5,6-difluoro-2-methylsulfanyl-benzothiazole in 8 mL methanol under nitrogen at 0-5° C., was added drop wise a solution of 1.019 g (1.658 mmol) oxone in 4 mL water. The reaction mixture was stirred at 0° C. for 1 h. The suspension was diluted with water (10 mL). The solid was filtered, washed with water and dissolved in dichloromethane. The solution was dried over Na2SO4, filtered, concentrated in vacuo and purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 130 mg (50.6%) of the title compound as white solid. MS(m/e): 234.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=2)[C:3]=1[NH2:21].[N:22]([O-])=O.[Na+]>>[Cl:1][C:2]1[C:3]2[N:21]=[N:22][N:9]([CH2:10][C:11]3[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1cc(CNc2nc(N)nc(Cl)c2N)cc(OC)c1
Reactant: O=N[O-]
Agent: [Na+]
Product: COc1cc(Cn2nnc3c(Cl)nc(N)nc32)cc(OC)c1

Procedure:
A solution of 6-chloro-N4-(3,5-dimethoxy-benzyl)-pyrimidine-2,4,5-triamine was treated with a cold aqueous solution of NaNO2, following the general procedure 2. HPLC RT was 6.185 min. 1HNMR (CDCl3): δ 6.54–6.53 (d, 2H), 6.41–6.40 (d, 1H), 5.58 (s, 2H), 5.54 (s, 2H), 3.78 (s, 6H).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>CO>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Product: O=C(CBr)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
13.50 g (corresponding to 59.66 mmol) of 4′-benzoyloxyacetophenone was dissolved in 1100 ml of methanol, and 34.52 g (corresponding to 71.59 mmol) of tetra-n-butylammonium tribromide was added thereto. The mixture was stirred overnight at room temperature, and was distilled off under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate and washed twice with water and then washed with an aqueous saturated sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (elution solvent: hexane/methylene chloride=1/1), to obtain 13.38 g (corresponding to 43.84 mmol) of 4′-benzoyloxy-2-bromoacetophenone (FIG. 5, Step 4).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)C>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:10][CH2:9]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CN1CCN(CCCN)CC1
Solvent: CCO
Product: CN1CCN(CCCNc2ncccc2[N+](=O)[O-])CC1
Temperature: 25 °C

Procedure:
In a 2 liter, three-necked flask fitted with condenser, dropping funnel, thermometer, magnetic stirrer and nitrogen inlet was placed 71.8 g. (0.456 mole) 1-(3-aminopropyl)-4-methyl piperazine and 150 ml. of ethanol. The solution was heated at reflux and a solution of 65.0 g. 2-chloro-3-nitropyridine dissolved in 500 ml. of warm ethanol was added dropwise over 90 minutes. The dark yellow reaction mixture was maintained at reflux of an additional hour then cooled to ambient temperature. The solvent was then removed in vacuo to obtain a yellow-brown semi-solid residue. The residue was partitioned between 200 ml. each of aqueous 1N HCl and methylene chloride, and aqueous phase washed with 100 ml. CH2Cl2. The aqueous portion was made basic with 6N NaOH and extracted with 3 × 250 ml. CH2Cl2. The combined organic layers were dried over Na2SO4 and the solvent evaporated to afford 2-[3-(4-methyl-1-piperazinyl)propylamino]- 3-nitropyridine as a red-yellow oil which crystallized on standing at room temperature; yield 82.9 g. (72%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccnc1CCl
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: Cc1cccnc1Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 84.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-3-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=[O:12])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1C(=O)N([Cl:21])C(=O)C1>CC#N>[Cl:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:10][C:11]([OH:13])=[O:12])[CH:2]=1
Reactant: O=C(O)Cn1ccc2cccnc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=C(O)Cn1cc(Cl)c2cccnc21
Temperature: 65 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a suspension of 2-(1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (100 mg) in MeCN (10 mL) was added NCS (91 mg) and the reaction mixture was stirred at 60° C. overnight and at 65° C. for 20 h. The solvent was removed in vacuo, the residue was taken up in DCM and the resulting precipitate was filtered off. The precipitate was further washed with DCM and dried in vacuo. 92 mg of grey solid was obtained. LC-MS (B): tR=0.66 min; [M+H]+: 211.02.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.C[SiH]([N:34](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)C>CCCCCC>[CH:35]1([NH:34][Si:2]([CH3:23])([CH3:22])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl) silane (9c)) (5.6340 g, 0.01633 moles) was stirred in hexane (100 mL) as NEt3 (2.9673 g, 0.02932 moles) and cyclohexylamine (1.6373 g, 0.01651 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.8969 g, 89.9 percent).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[Br-:15].[Na+].[CH3:17][C:18]1[C:26]([CH3:28])([CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:29]([OH:32])(=[O:31])=[O:30])[CH:24]=2)[N:19]=1.[K]>S1(CCCC1)(=O)=O.CC(C)=O>[Br-:15].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:19]1[C:20]2[C:25](=[CH:24][C:23]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:22][CH:21]=2)[C:26]([CH3:28])([CH3:27])[C:18]=1[CH3:17])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Reactant: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)C
Agent: [Br-]
Agent: [K]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC(C)=O
Product: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccc(S(=O)(=O)O)cc2C1(C)C
Temperature: 100 °C
Reaction time: 5 h

Procedure:
3,5-Dinitrobenzyl chloride (22.1g, 102 mmol) and sodium bromide (10.5 g, 102 mmol) were added to 2,3,3-trimethyl-5-sulpho-indole, potassium salt (5.0 g, 20.4 mmol) in sulpholane (25 ml). The reaction mixture was stirred at 100° C. for 5 hours. The solution was then cooled to room temperature and acetone (300 ml) was added to the reaction flask. A brown precipitate was formed which was collected by filtration and then purified by reverse phase HPLC. This gave a beige solid which was dried in vacuo. UV (water/acetonitrile): λmax=283 nm. MS: m/z=420 (C18H18N3O7S=420.4).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1c(C)cc(C)cc1/C=C/C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1c(C)cc(C)cc1CCC(=O)O
Yield: 91.9 %

Procedure:
In acetic acid (80 mL) were suspended (E)-3-(2-methoxy-3,5-dimethylphenyl)propenoic acid (9.60 g, 46.5 mmol) and 10% palladium-on-carbon (hydrous) (0.60 g) and the suspension was stirred in a hydrogen atmosphere at 60° C. for 14 hours. The catalyst was then filtered off and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethanol to provide 8.90 g of the title compound. Yield 91%.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+]>C(O)C.O>[F:10][C:8]1[CH:9]=[C:2]([CH3:1])[C:3]([CH2:4][C:12]#[N:13])=[C:6]([CH3:11])[CH:7]=1
Reactant: [C-]#N
Reactant: Cc1cc(F)cc(C)c1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(F)cc(C)c1CC#N

Procedure:
A solution of 1.86 g (9 mmol) 2,6-dimethyl-4-fluoro-benzyl bromide and 0.420 g (9 mmol) sodium cyanide in 21 ml ethanol/water 6:1 was heated to reflux for 4h. The cooled reaction mixture was concentrated and extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated. Filtration of the residue through a silica gel pad with heptane/ethyl acetate 1:1 provided (4-fluoro-2,6-dimethyl-phenyl)-acetonitrile as colourless solid: MS (EI): 163.1 (M+.), 148.1 ((M-CH3)+.), 136.1 ((M-HCN)+., 100%).