Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:13]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[CH2:22][CH3:23])=[C:12]([NH:25][CH:26]2[CH2:28][CH2:27]2)[N:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1B(O)O>O.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>[CH:26]1([NH:25][C:12]2[C:13]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=3[CH2:22][CH3:23])=[C:8]([C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][C:40]=3[Cl:42])[N:9]=[CH:10][N:11]=2)[CH2:28][CH2:27]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (2 ml)/water (0.7 ml) was added to N-(4-chloro-6-cyclopropylaminopyrimidin-5-yl)-2-ethylnicotinamide (0.41 mmol), sodium carbonate (3 eq) and 2,4-dichlorophenylboronic acid (2 eq). 5 mol % of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The mixture was then diluted with water and extracted 3× with methylene chloride, and the combined organic phases were washed with aqueous NaHCO3 solution, dried 20 over Na2SO4, filtered and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14](O)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:29])=O>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14]([Cl:29])(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonic acid (2.16 g, 7.21 mmol) obtained in step 2 was dissolved in dichloroethane (20 mL), and the solution was stirred at 100° C. for 4 hours after adding triethylamine (2.01 mL, 14.4 mmol) and phosphorus oxychloride (1.34 mL, 14.4 mL). The reaction mixture was extracted with chloroform after adding water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 6-chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.73 g, yield 75%).
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13](=[O:53])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]([NH:26][CH2:27][CH:28]([C:37]2[CH:42]=[CH:41][C:40]([O:43]CC3C=CC=CC=3)=[C:39]([CH2:51][OH:52])[CH:38]=2)[O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])([CH3:25])[CH3:24])[CH:17]=1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[Si:30]([O:29][C@H:28]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([CH2:51][OH:52])[CH:38]=1)[CH2:27][NH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:13]([OH:53])=[O:12])[CH:21]=[CH:20][CH:19]=1)([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:32])[CH3:31]
Reactant: CC(C)(Cc1cccc(C=CC(=O)OCc2ccccc2)c1)NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c(CO)c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(Cc1cccc(CCC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 90 %

Procedure:
Ammonium formate (139 mg, 2.20 mmol) and palladium (II) hydroxide (50 mg) was added to a solution of 3-(3-{2-[2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)ethylamino]-2-methyl-propyl}-phenyl)-acrylic acid benzyl ester (preparation 143), (300 mg, 0.44 mmol) in ethanol (10 mL) and the mixture was heated under reflux for 30 minutes. The reaction mixture was then cooled, filtered through Arbocel® and concentrated in vacuo to afford the title compound in 90% yield, 200 mg. 1H NMR (400 MHz, CD3OD) δ: 7.30 (1H, s), 7.20 (1H, m), 7.18 (1H, d), 7.09 (2H, m), 7.00 (1H, d), 6.78 (1H, d), 4.88 (1H, m), 4.63 (2H, m), 3.11 (2H, m), 2.83 (4H, m), 2.48 (2H, m), 1.23 (6H, s), 0.81 (9H, s), −0.03 (3H, s), −0.18 (3H, s) ppm; LRMS ESI m/z 502 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10]C)=[O:9])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([CH3:17])[CH:4]=1.[OH-].[Na+]>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:17])[C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(OC)cc(C)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: COC(=O)c1c(C)cc(OC)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of compound L (50.0 g, 210 mmol) in 1,2-dimethoxyethane (260 mL) was added 8% aqueous NaOH (262 mL) at 0° C. The mixture was stirred at room temperature for 1 hour, washed with ethyl acetate and acidified to pH 2 using 3 mol/L HCl. The precipitate was filtered and washed with water to give compound M (40.0 g). The filtrate was extracted with ethyl acetate 3 times. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. Filtration and evaporation of the solvent gave compound M (5.47, 96% total yield) as a white powder. 1H NMR (CDCl3, 400 MHz): δ 2.35 (3H, s), 3.86 (3H, s), 3.90 (3H, s), 6.97 (1H, d, J=2.4 Hz), 7.39 (1H, d, J=2.4 Hz). EIMS (+): 224 [M]+
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)=[CH:20][CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)c1ccncc1
Product: c1cc(-c2ccncc2)c2[nH]c3c(c2c1)CN1CCC3CC1

Procedure:
The product of Example 1B (100 mg, 0.34 mmol) and pyridine-4-boronic acid (52 mg, 0.38 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.06-2.17 (m, 4 H), 3.06-3.18 (m, 3 H), 3.23-3.29 (m, 2 H), 4.30 (s, 2 H), 7.13 (t, J=7.6 Hz, 1 H), 7.17-7.20 (m, 1 H), 7.41 (dd, J=7.6, 1.2 Hz, 1 H), 7.70-7.74 (m, 2 H), 8.58-8.64 (m, 2 H); MS (APCI) m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C:15]1([NH:18]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[C:40](=[O:43])[NH:41][CH3:42])[CH:31]=1>CCO.[Pd]>[NH2:18][C:15]1([CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:29][C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[C:36]([C:40]([NH:41][CH3:42])=[O:43])=[CH:35][CH:34]=[CH:33]5)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:16][CH2:17]1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NC(=O)OCc6ccccc6)CC5)c(OC)cc34)ccc12
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N)CC5)c(OC)cc34)ccc12

Procedure:
The product of Example 1 (100 mg) was mixed with Pd/C (10%, 40 mg) in EtOH (30 ml) and hydrogenated at 50 psi for 12 hours. The reaction was filtered through Celite and evaporated to give the titled product. Mass: (M+1), 444
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[O:8][C:7]=1[CH3:17])=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH:11]1([C:9]2[O:8][C:7]([CH3:17])=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1cc(C2CCCCC2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(C2CCCCC2)cc1C(=O)O
Yield: 76.2 %

Procedure:
A solution of 5-cyclohexyl-2-methyl-furan-3-carboxylic acid ethyl ester (143 mg, 0.605 mmol) and 2N sodium hydroxide (1.5 mL, 3.0 mmol) in 3 mL ethanol and 1.5 mL water was heated to reflux for 1 hour. The reaction mixture was cooled, pH adjusted to 1 with 1N HCl and extracted with CH2Cl2 (5×40 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 5-cyclohexyl-2-methyl-furan-3-carboxylic acid (96 mg, 76%).
Reaction SMILES: Cl.[F:2][C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)CCC2(OCCO2)CC1.C(=O)(O)[O-].[Na+].[O:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>>[F:2][C:3]1([C:13]2[N:18]=[CH:17][C:16]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][N:29]=4)[C:26]=3[CH3:27])=[O:21])=[CH:15][CH:14]=2)[CH2:46][CH2:47][O:43][CH2:44][CH2:45]1
Reactant: Cc1c(C(=O)Nc2ccc(C3(F)CCC4(CC3)OCCO4)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: C1CCOC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1c(C(=O)Nc2ccc(C3(F)CCOCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 6 h

Procedure:
3N Hydrochloric acid aqueous solution (12 ml) was added at room temperature to a solution of N-[6-(8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (308 mg) described in Example K65 in tetrahydrofuran (12 ml), and stirred at the same temperature for six hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added, the solvent was evaporated, water was added and the precipitated solid was filtered to give the titled compound (257 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CCCCCC>C1COCC1>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][CH2:4][CH2:3][OH:2])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)CCC1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N2CCCC2CCCO)cc1

Procedure:
Reduction of (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from diethyl ether/hexane yielded (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanol, colorless oil, MS: m/e=284.2 (M+H+).
Reaction SMILES: ClC1N=CC2CN(C(=O)C)C3C=CC=CC=3C=CC=2C=1.COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.[C:38]([N:41]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[CH:45][C:44]2[N:53]=[C:54]([C:58]3[CH:59]=[N:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)[C:55](F)=[CH:56][C:43]=2[CH2:42]1)(=[O:40])[CH3:39]>>[C:38]([N:41]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH:46]=[CH:45][C:56]2[CH:55]=[C:54]([C:58]3[CH:59]=[N:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)[N:53]=[CH:44][C:43]=2[CH2:42]1)(=[O:40])[CH3:39]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Agent: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Agent: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1ccc(-c2cc3c(cn2)CN(C(C)=O)c2ccccc2C=C3)cn1
Yield: 65 %

Procedure:
The title compound (16.3 mg, 65%) was prepared from 41D (20 mg, 0.07 mmol) and 2A (24.7 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.453 min; LCMS Found: (M+H)+=358.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7][NH:6][CH2:5]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30](=[O:32])[CH3:31]>C(#N)C.ClCCl>[CH3:1][O:2][CH2:3][CH:4]1[CH2:5][N:6]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:7][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[O:21]1
Reactant: COCC1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COCC1CN(CC(C)=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1

Procedure:
To a mixture of tert-butyl 10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate and K2CO3 (115 mg, 0.832 mmol) in acetonitrile (1.4 mL) was added 1-bromopropan-2-one (304 mg, 2.00 mmol). The reaction mixture was heated under argon in a sealed tube for 16 h. The mixture was cooled, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to provide tert-butyl 2-(methoxymethyl)-4-(2-oxopropyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate. ESI-MS m/z calc. 356.2. found 357.3 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: Br[C:2]1[N:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)#[CH:16]>>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][N:3]1[C:4]([Cl:8])=[C:5]([Cl:7])[N:6]=[C:2]1[C:16]#[C:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCOC(=O)Cn1c(Br)nc(Cl)c1Cl
Reactant: C#Cc1ccccc1
Product: CCOC(=O)Cn1c(C#Cc2ccccc2)nc(Cl)c1Cl

Procedure:
The title compound, MS: m/e=323.0 (M+H+) was prepared in accordance with the general method of example 1b from ethyl (2-bromo-4,5-dichloroimidazole-1-yl)acetate and ethynylbenzene.
Reaction SMILES: CI.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[C:7]2[CH3:15].[C:16]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:16])[C:9](=[O:14])[CH:8]=[C:7]2[CH3:15]
Reactant: Cc1cc(=O)[nH]c2ccc(F)cc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(=O)n(C)c2ccc(F)cc12
Reaction time: 8 h
Yield: 68.6 %

Procedure:
MeI (130 mg, 0.914 mmol) was added into a suspension of 6-fluoro-4-methylquinolin-2(1H)-one (135 mg, 0.762 mmol) and Cs2CO3 (248 mg, 0.762 mmol) in DMF (10 mL). The reaction mixture was stirred overnight and partitioned between Na2CO3 solution and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was washed with hexanes and dried to give 6-fluoro-1,4-dimethylquinolin-2(1H)-one (100 mg, 68%) as a white solid which was used without purification.
Reaction SMILES: [C:1]1([C:7]2(CC(O)=O)[O:11][C:10]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C1C=CC=CC=1>[CH2:9]([O:8][C:7](=[O:11])[CH2:1][CH2:2][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:11][C:10]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:9]=2[O:8]1)[CH3:10]
Reactant: O=C(O)CC1(c2ccccc2)Oc2ccc(Cl)cc2O1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC1(c2ccccc2)Oc2ccc(Cl)cc2O1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
11.7 g. of (2-phenyl-5-chloro-1,3-benzodioxol-2-yl)-acetic acid mixed with 50 cc. of anhydrous benzene are refluxed with 10 cc. of SOCl2 for 3 hours. The solvent and the excess of SOCl2 are removed under vacuum. The residual oil mixed with 150 cc. of anhydrous ether is added in drops to an ether solution of diazomethane, which is ice cooled to maintain the temperature under 2°-3°C. After 24 h, the ether is removed under vacuum and the residue is mixed with 100 cc. of ethanol. The mixture is heated at 50°C., and 2 g. of Ag2O are added. After 2 hours, the product is treated with animal charcoal, filtered and dried. It is then fractionated and the desired product boils at 200°-207°C./0.4 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11](O)=[O:12].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][CH2:11][OH:12]
Reactant: O=C(O)Cc1cc(F)c(F)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
A solution of 2-(2,4,5-trifluorophenyl)acetic acid (1 g, 5.26 mmol) in dry THF (20 mL) was carefully added over 2 min to solution of 2M LAH (10.52 mL, 10.52 mmol) at 0° C. The reaction mixture was allowed to warm to rt and was stirred for 6 h. The reaction was quenched with 0.5 mL of water (stir for 10 min), 0.5 mL of 15% NaOH/water (stir for 10 min), and then 1.0 mL of water. After stirring for 18 h, the mixture was filtered through celite. The filtrate was concentrated in vacuum. The residue was dried under high vacuum for 16 h to afford 2-(2,4,5-trifluorophenyl)ethanol (850 mg, 4.83 mmol, 92% yield) as a clear viscous oil, which was used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.11 (ddd, J=10.3, 8.7, 7.2 Hz, 1H), 6.93 (td, J=9.7, 6.6 Hz, 1H), 3.87 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H).
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH2:9].Br.[OH-].[Na+].[C:19]1(C)[CH:24]=CC=C[CH:20]=1>>[C:10]1(/[CH:2]=[C:3]2/[CH:4]([N:9]3[CH2:24][CH2:19][CH2:20]3)[CH2:5][CH2:6][CH2:7][CH2:8]/2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC1CCCCC1C(O)c1ccccc1
Reactant: Cc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: C(=C1\CCCCC1N1CCC1)\c1ccccc1
Yield: 30 %

Procedure:
A mixture of 2.5 g (9.5 mmoles) of cis-N-(3-hydroxypropyl)-N-[2-[hydroxy(phenyl)methyl][cyclohexyl]amine, 10 ml of toluene and 6.45 g of 48% v/v aqueous hydrogen bromide solution was stirred and heated on a steam bath for 3.5 hr. The resulting solution was cooled, basified with 20% sodium hydroxide solution and extracted with chloroform. The chloroform extract was washed with water, and saturated sodium chloride solution and then dried over magnesium sulfate and evaporated. The residue, 2 g, was chromatographed by high pressure liquid chromatography (HPLC) procedures using a Merck silica gel, size C column and 10% v/v methanol/in chloroform/1% v/v ammonium hydroxide mixture as eluting liquid, collecting 20 ml fractions. Fractions 1 to 14 gave no product material. Fractions 15 to 25 gave 0.686 g (30% yield) of (±)-(E)-1-[2-(phenylmethylene)cyclohexyl]azetidine, which was identified by NMR analysis comparison with the NMR of standard, authentic compound. Fractions 26 to 31 gave 0.25 g of a mixture, and fractions 32 to 50 gave 0.286 g of N-(3-hydroxypropyl)-N-[2-(phenylmethylene)cyclohexyl]amine which was identified by NMR comparison with a known standard sample, and also by conversion to its hydrochloride salt which was identical to a standard sample by NMR, UV and IR spectral analysis comparisons.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([N+:21]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c(N)c1
Yield: 88.6 %

Procedure:
3-Amino-4-(2-tert-butoxycarbonylamino-ethylamino)-benzoic acid methyl ester (525.0 mg) was prepared by following General Procedure B starting from 4-(2-tert-butoxycarbonylamino-ethylamino)-3-nitro-benzoic acid methyl ester (650.0 mg) and Pd/C (20% by weight, 130.0 mg) in MeOH:EtOAc (1:1, 6.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C-:17]#[N:18].[K+]>C(#N)C>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][C:17]#[N:18])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: N#CCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 98.1 %

Procedure:
A solution of 9-chloromethyl-anthracene (10.0 g, 44.11 mmol) and potassium cyanide (28.72 g, 441.1 mmol) in acetonitrile (1.6 L) was heated to reflux for 2 hours. The mixture was cooled to room temperature, filtered and concentrated. The residue was dissolved in CH2Cl2, washed with water, dried over MgSO4 and concentrated to give anthracen-9-yl-acetonitrile as yellow crystals (9.40 g, 98% yield). 1H NMR (CDCl3) δ 8.53 (1H, s), 8.18 (2H, d), 8.07 (2H, d), 7.65 (2H, dd), 7.54 (2H, dd), 4.60 (2H, s).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[OH:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:7]=1
Reactant: OCc1cccnc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccnc3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (50 mg; 0.129 mmol), intermediate 42.1, and 3-(hydroxymethyl)-pyridine (57 mg; 0.515 mmol), example 74 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:17]([CH:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[CH2:11]3)=[CH:4][CH:3]=1.[CH2:25]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:23][CH:22]([CH3:24])[CH:17]([N:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:31][CH:32]=4)=[CH:7][CH:6]=3)[CH:9]=2)[CH2:13]1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C(C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)CN(C(C(=O)OC)C(C)C)C4)cc2)cc1
Yield: 22 %

Procedure:
The compound of example 675 was prepared analogous to the compound of example 663 by reaction of compound of example 673 with 4-(n-pentyl)benzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([S:14]([NH2:17])(=[O:16])=[O:15])([C:10]([OH:13])([CH3:12])[CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.[CH3:22][O:23][C:24](OC)(OC)OC>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[C:10]([CH3:12])([CH3:11])[O:13][C:22]([O:23][CH3:24])=[N:17][S:14]2(=[O:15])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(O)C(C)(c1cccc(Br)c1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A suspension of 1.10 g of 2-(3-bromophenyl)-3-hydroxy-3-methylbutane-2-sulfonamide in 10 ml of tetramethoxymethane was admixed with 2 ml of acetic acid and stirred at 100° C. for 5 hours. After the removal of the solvent under reduced pressure, the crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (0.61 g) with a molecular weight of 362.2 g/mol (C13H16BrNO4S).