Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cccnc1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cccnc3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 26, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 3-bromopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13](=[O:16])[CH2:14][CH3:15])[CH:7]=[CH:6]2.[CH3:17][O:18][C:19](=[O:28])[C@@H:20]([C@H:22]([C:24]([O:26][CH3:27])=[O:25])O)[OH:21].C(OC)(OC)OC.CS(O)(=O)=O>C([O-])([O-])=O.[Na+].[Na+]>[CH3:27][O:26][C:24]([C@H:22]1[C@H:20]([C:19]([O:18][CH3:17])=[O:28])[O:21][C:13]([CH2:14][CH3:15])([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[O:16]1)=[O:25]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: CCC(=O)c1ccc2cc(OC)ccc2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CCC1(c2ccc3cc(OC)ccc3c2)O[C@@H](C(=O)OC)[C@H](C(=O)OC)O1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
1-(6-methoxy-2-naphthyl)-propan-1-one (46.5 g; 0.217 moles), L(+)tartaric acid dimethyl ester (300 g), trimethyl orthoformate (94 g; 0.887 moles) are gradually heated up to complete solution. Methanesulphonic acid (1.48 g; 0.0154 moles) is then added and the obtained solution is refluxed for 2 hours; it is cooled at room temperature and the reaction mixture is slowly added to a 10% solution of Na2CO3 (500 ml). It is extracted with methylene chloride and the organic extracts are repeatedly washed with water. The organic phase is dried on Na2SO4 and the solvent is evaporated under reduced pressure. The residue is crystallized from methanol (250 ml). The desired product is obtained (51.68 g; 0.138 moles; yield 63.6%) having the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=O)[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:24][CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])=[O:13])[C:8]([CH3:14])=[C:7]2[C:3]=1[C:4]1[CH:18]=[C:17]([CH3:19])[CH:16]=[N:15][C:5]=1[NH:6]2
Reactant: Cc1cnc2[nH]c3c(C)c(C(=O)O)cc(Cl)c3c2c1
Reactant: CN(C)CCN
Product: Cc1cnc2[nH]c3c(C)c(C(=O)NCCN(C)C)cc(Cl)c3c2c1

Procedure:
The title compound was synthesized from 5-chloro-3,8-dimethyl-9H-pyrido[2,3-b]indole-7-carboxylic acid and N,N-dimethylethane-1,2-diamine using an analogous procedure to that described in the preparation of Compound 88. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.20 (s, 6H) 2.42 (t, J=6.69 Hz, 2H) 2.49 (br. s., 3H) 2.55 (s, 3 H) 3.35 (d, J=6.57 Hz, 2H) 7.18 (s, 1H) 8.31 (t, J=5.56 Hz, 1H) 8.40 (d, J=2.02 Hz, 1H) 8.53 (s, 1H) 12.14 (s, 1H). [M+H] calc'd for C18H21ClN4O 345; found, 345.4.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])([O-])=O.[Sn](Cl)Cl.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C(O)C.O.C(OCC)(=O)C>[NH2:1][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[CH:10][C:11]=2[Cl:13])[NH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N
Temperature: 25 °C
Yield: 97.6 %

Procedure:
Dissolve 3-nitro-2-carbethoxy-4,6-dichloroindole (38.1 g) in ethanol (1 L) and add tin (II) chloride dehydrate (163 g). Warm to between 65° and 65° C. for 4 to 5 hours. Cool to room temperature and pour into a mixture of ethyl acetate (3 L) and water (2 L). Add solid potassium carbonate and stir occasionally until the carbon dioxide evolution ceases. Filter throught Celite and separate the organic phase of the filtrate. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an off-yellow solid (33.5 g, 97.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:47])([CH3:46])[C:8](=[O:45])[N:9]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[O:33][CH2:34][CH2:35][CH2:36][O:37]C4CCCCO4)=[CH:22][C:21]=3[F:44])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:47])([CH3:46])[C:8](=[O:45])[N:9]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[O:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:22][C:21]=3[F:44])=[O:19])[CH2:14][CH2:13]2)=[N:4][CH:3]=1
Reactant: CC1(C)Cc2ncc(Cl)cc2N(C2CCN(C(=O)c3ccc(-c4cc(F)ccc4OCCCOC4CCCCO4)cc3F)CC2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2ncc(Cl)cc2N(C2CCN(C(=O)c3ccc(-c4cc(F)ccc4OCCCO)cc3F)CC2)C1=O
Reaction time: 4 h
Yield: 88.1 %

Procedure:
To a methanol solution (10 ml) of 7-chloro-1-[1-({3,5′-difluoro-2′-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]biphenyl-4-yl}carbonyl)piperidin-4-yl]-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (300 mg) was added at room temperature p-toluenesulfonic acid monohydrate (8.7 mg), followed by stirring for 4 hours. After the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 7-chloro-1-(1-{[3,5′-difluoro-2′-(3-hydroxypropoxy)biphenyl-4-yl]carbonyl}piperidin-4-yl)-3,3-dimethyl-3,4-dihydro-1,5-naphthyridin-2(1H)-one (231 mg).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)[CH3:2].[BH4-].[Na+].C(O)(=O)C.O>O1CCCC1>[CH2:1]([NH:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1CC[C@H](CNC(C)=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCNC[C@H]1CC[C@H](CC(=O)OCC)CC1
Reaction time: 6 h

Procedure:
Ethyl trans-{4-[(acetylamino)methyl]cyclohexyl}acetate (1.19 g, 4.93 mmol) was dissolved in tetrahydrofuran (25 mL), the solution was added with sodium borohydride (932 mg, 24.66 mmol), the mixture was added dropwise with a solution of acetic acid (1.48 g, 24.66 mmol) in tetrahydrofuran (25 mL) over 1 hour under reflux by heating, and the mixture was stirred at the same temperature for 6 hours. The reaction mixture was added dropwise with water with stirring under ice cooling, and the reaction was thereby quenched. The reaction mixture was made alkaline with 2 M aqueous sodium hydroxide, and extracted with ethyl acetate, and the organic layer was successively washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting crude product of ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate was dissolved in ethanol (20 mL), the solution was added with 4 M hydrochloric acid in ethyl acetate (6 mL), and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was successively washed with 2 M sodium hydroxide, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the objective ethyl trans-{4-[(ethylamino)methyl]cyclohexyl}acetate as pale brown oil (1.12 g, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(C1OC(Cl)=CC=1)=O)C.C(OC(N1CCC2N([CH2:53][C:54]3[O:55][C:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])=[CH:57][CH:58]=3)N=C(C3C=CC(Cl)=CC=3)C=2CC1)=O)(C)(C)C>>[CH2:62]([O:61][C:59]([C:56]1[O:55][C:54]([CH2:53][N:13]2[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)=[CH:58][CH:57]=1)=[O:60])[CH3:63]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CCOC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)o1
Agent: CCOC(=O)c1ccc(Cl)o1
Product: CCOC(=O)c1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCNCC3)o1

Procedure:
The title compound (0.008 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 5-chloro-furan-2-carboxylic acid ethyl ester (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 3-(4-chloro-phenyl)-1-(5-ethoxycarbonyl-furan-2-ylmethyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3O3, 399.13; found, m/z 400.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.44 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.00 (d, J=3.5 Hz, 1H), 6.21 (d, J=3.5 Hz, 1H), 5.09 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.21-3.19 (m, 2H), 3.11-3.09 (m, 2H), 2.96-2.94 (m, 2H), 2.61-2.59 (m, 2H), 1.24 (t, J=7.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[N:6]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:7]([CH3:20])=[C:8]([C:18]#[N:19])[C@@H:9]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.C1COCC1.Cl[C:38]([O:40][CH3:41])=[O:39]>N1C=CC=CC=1>[C:18]([C:8]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=2)[N:4]2[N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][CH3:41])[N:31]=[C:5]2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=2)[C:7]=1[CH3:20])#[N:19]
Reactant: COC(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (30 mg, 71 μmol) was dissolved in a mixture of abs. THF (3 ml) and abs. pyridine (57.5 μl). At room temperature, pyridine (5×57 μl) and methyl chloroformate (5×33.6 mg, 5×356 μmol; 25 eq.) were added in a plurality of portions. The mixture was then heated at 80° C. for 12 h. Once HPLC analysis showed substantial conversion, the reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (31.1 mg, 91% of theory).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C1COCC1.O.C(OCC)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-nitropyridine (10 g, 63.3 mmol) was dissolved in 150 mL of THF. 20 mL of piperidine was then added and the resulting mixture was stirred for 18 hours at room temperature. The reaction mixture with copious precipitate was then diluted with 200 mL of water and 100 mL of diethyl ether. The layers were thoroughly mixed and separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The bright yellow solid was redissolved in 35 mL of dichloromethane and, with vigorous stirring, hexanes were added until the product began to precipitate. The bright yellow solid was collected by filtration and dried to afford 12.5 g of 5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][C:3]=1[F:17].[H-].[Na+].[Cl-].C1(OP(=O)(O)OC2C=CC=CC=2)C=CC=CC=1.[N+:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])#[C-:39].C(=O)=O>CN(C)C=O.C(O)(=O)C.CCCCCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11]3[N:12]([CH:39]=[N:38][C:40]=3[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:17]
Reactant: O=C1Nc2ccc(F)c(Cl)c2C(=O)N2CC[C@@H]12
Reactant: [C-]#[N+]CC(=O)OCC
Agent: O=C=O
Agent: O=P(O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 41.2 %

Procedure:
25.4 g (100 mmol) of (S)-5-chloro-6-fluoro-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 125 ml of N,N-dimethylformamide, treated at -30° with 4.8 g (110 mmol) of sodium hydride dispersion (55-65% in oil, washed with n-hexane) and deprotonated for 40 min. at -30° to -18°. A solution of 26.86 g (100 mmol) of phosphoric acid diphenyl ester chloride in 5 ml of N,N-dimethylformamide was added at -60° and the mixture was stirred at max. -45° for 35 min. In the meanwhile and separately, 12.3 g (110 mmol) of potassium tert.-butylate were dissolved in 30 ml of N,N-dimethylformamide and treated at -60° C. with 12.2 g (107 mmol) of ethyl isocyanoacetate. The deprotonated ethyl isocyanoacetate was cooled to -70° and the reaction mixture was added dropwise using a dropping funnel cooled with dry ice at max. -65° within 5/4 hours. The mixture was stirred in an acetone/dry ice bath for 1 hour, neutralized with 12 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.2 l), dried over magnesium sulfate and evaporated to dryness. By chromatography of the residue on 1.5 kg of silica gel while eluting with ethyl acetate there were obtained 14.4 g (41%) of ethyl (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxylate of m.p. 161°-163°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].Cl[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1)[CH2:23][CH2:24][CH3:25]
Reactant: Clc1cnccn1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
n-Butyllithium (30.0 ml, 1.6M in hexanes, 48.0 mmol) was added dropwise to a cooled (−40° C.) solution of diisopropylamine (7 ml, 50.1 mmol) in tetrahydrofuran (30 ml), so as to maintain the temperature below −30° C. Once addition was complete, the solution was allowed to warm to room temperature for 2 minutes, then re-cooled to −70° C. Tri-n-butyltin hydride (12 ml, 45.8 mmol) was added dropwise over 10 minutes, and once addition was complete, the reaction was stirred at −60° C. for 2 hours. A solution of 2-chloropyrazine (5.0 g, 43.7 mmol) in tetrahydrofuran (5 ml) was added, and the reaction allowed to warm to room temperature. Aqueous ammonium chloride solution was added to quench the reaction, followed by dilution with ethyl acetate. The resulting suspension was filtered through Celite®, and the filtrate separated. The organic phase was washed with brine, dried (MgSO4), and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to afford the title compound, (800 mg, 5%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][N:12]=1)[C:6](OC)=[O:7]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(OC)c1
Solvent: C1CCOC1
Product: COc1cc(CO)ccn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
To a 100-mL round-bottomed flask was added methyl 2-methoxyisonicotinate (2.04 mL, 14.12 mmol, Aldrich, St. Louis, Mo.) and borane methyl sulfide complex (4.02 mL, 42.4 mmol, Aldrich, St. Louis, Mo.) in THF (30 mL). The reaction mixture was stirred at 70° C. for 18 h, cooled to 0° C. and quenched by the addition of MeOH (5 mL), followed by 1N NaOH (20 mL). The reaction mixture was extracted with EtOAc (2×50 mL), the organic extract was washed with saturated NaCl (20 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 60% EtOAc/hexanes to give (2-methoxy-4-pyridinyl)methanol (1.56 g) as colorless oil.
Reaction SMILES: [CH2:1]([N:3]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][NH:14]2)=[N:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2].C[CH2:30][N:31](C(C)C)C(C)C.CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:1]([N:3]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:4]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH2:19][C:20]([NH:31][CH3:30])=[O:22])=[CH:15][NH:14]2)=[N:11][CH:12]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]cc(CC(=O)O)c2=O)nc1
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCN(c1ccccc1)S(=O)(=O)c1ccc(-n2[nH]cc(CC(=O)NC)c2=O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.2 %

Procedure:
To a mixture of 0.28 g (0.7 mmol) of (2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)acetic acid, 0.61 mL (3.48 mmol) of DIEA and 0.8 mL (1.4 mmol) of methylamine (2N solution in THF) in 2 mL of DCM is added at 0° C. 0.33 g (1.04 mmol) of TBTU. After stirring for 3 hours at room temperature, the medium is taken up in 500 mL of DCM, washed successively with 0.1N HCl (2×40 mL), saturated NaHCO3 solution (2×40 mL) and brine (30 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a 95/5 DCM/MeOH mixture. 18 mg of 2-(2-{5-[ethyl(phenyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-N-methylacetamide are obtained in the form of a brown powder.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:3][C:4]#[CH:5].C(NCC)C.Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1>[Cu]I>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:5]#[C:4][CH2:3][CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:24]=1
Reactant: Brc1cccnc1
Reactant: C#CCC(O)CCCCOC1CCCCO1
Agent: [Cu]I
Solvent: CCNCC
Product: OC(CC#Cc1cccnc1)CCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5.84 g (25.8 mmol) 4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne, 4.7 mL diethylamine, 10 mL (100 mmol) 3-bromopyridine, 0.032 g copper (I) iodide, and 0.187 g bis-triphenylphosphine palladium (II) chloride is stirred at room temperature for 18 hours. The solvent is evaporated and the residue taken up in ether. The ether layer is washed with saturated aqueous sodium bicarbonate, water, brine, dried, filtered and evaporated to get an amber oil which is purified by chromatography using ether as the eluent to give 1-(3-pyridyl)-4-hydroxy-8-(2-tetrahydropyranyloxy)-1-octyne; NMR (CDCl3): delta 4.6 (brs,1H), 2.6 (d,2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([C:11]([OH:13])=[O:12])=[CH:8][C:7](=[O:14])[C:6]=2[CH:15]=1>C1C=CC=CC=1.[Rh].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7](=[O:14])[C:6]=2[CH:15]=1
Reactant: O=C(O)c1cc(=O)c2cc(F)ccc2o1
Agent: [Rh]
Solvent: CO
Solvent: c1ccccc1
Product: O=C1CC(C(=O)O)Oc2ccc(F)cc21
Reaction time: 0.25 h

Procedure:
(+)-2,3-O-isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphyno)butane (120 mg, 0.0240 mmol) was added to a solution of dichloro-bis-[(1,3)-cyclooctadiene]-dirhodium(I) (59.2 mg, 0.0120 mmol) in dry benzene (0.5 ml) under argon atomosphere and the mixture was stirred for 15 minutes to prepare an optical active rhodium catalyst. The benzene solution (catalyst) was added to a suspension of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid (1.00 g, 4.80 mmol, obtained in Example 5) in methanol (30 ml) under argon atmosphere. Gaseous phase was changed for H2, and the mixture was stirred for 24 hours under H2 (4 kg/cm2) at 40° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:24]([O:25][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)[CH2:23][N:22]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:21][CH:20]2[CH2:44][OH:45])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:20]([CH2:44][O:45][CH2:47][C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)[CH2:21][N:22]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:23][CH:24]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CC(COCc2cccnc2)C(c2ccc(COCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3SR,4RS,5RS)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 3-(chloromethyl)-pyridine there was obtained tert-butyl (3RS,4RS,5SR)-4-[4-(2-benzyloxy-ethoxymethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-5-(pyridine-3-ylmethoxymethyl)-piperidine-1-carboxylate as a colourless oil; MS: 703 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[O:6]C(=O)[CH:4]=1.[CH3:14][O-:15].[Mg+2].[CH3:17][O-:18].Cl>>[F:10][C:9]([F:12])([F:11])[C:7](=[O:6])[CH2:8][C:3](=[O:2])[CH2:4][C:14]([O:18][CH3:17])=[O:15]
Reactant: COc1cc(C(F)(F)F)oc(=O)c1
Reactant: C[O-]
Agent: Cl
Agent: [Mg+2]
Product: COC(=O)CC(=O)CC(=O)C(F)(F)F
Yield: 25 %

Procedure:
A solution of 4-methoxy-6-trifluoromethylpyran-2-one (10 g, 52 mmol) in a methanolic magnesium methanolate solution (8.5% Mg(OMe)2, 62.8 g, 61 mmol) was heated under reflux for 2 hours. Concentrated aqueous HCl (25.5 g, 250 mmol) was added to the reaction solution, and the mixture was heated under reflux for a further 2 hours, then cooled and concentrated in vacuo to about 20% of the initial volume. The residue was mixed with 10 mL each of methylene chloride and water. The organic phase was separated off, washed with water, dried over sodium sulfate and concentrated. Kugelrohr distillation at 0.04 mbar and about 160° C. afforded methyl 6,6,6-trifluoro-3,5-dioxohexanoate (2.8 g, 13 mmol, 26%) as a pale yellow oil.