Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:9]([CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH:17]=[CH2:18])[CH:7]=[CH2:8].[C:20]([O-])(=[O:22])C.[Na+]>CN(C=O)C>[CH2:16]([C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:10]=1[N:9]([CH2:6][CH:7]=[CH2:8])[CH3:19])[CH:20]=[O:22])[CH:17]=[CH2:18]
Reactant: CC(=O)[O-]
Reactant: C=CCc1ccccc1N(C)CC=C
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCc1cc(C=O)ccc1N(C)CC=C
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To dry DMF (25 ml) is added phosphorous oxychloride (15.4 g, 0.10 mol) at 0°-5° C. with mechanical stirring over 0.5 hours. N,2-Diallyl-N-methylaniline (18.7 g, 0.10 mol) in DMF (10 ml) is added in a slow stream with stirring. The mixture is heated to 100° C. with stirring for two hours. The mixture is cooled, poured into ice water (200 ml) and neutralized by slow addition of saturated sodium acetate (150 ml) with stirring. The mixture is extracted with ether two times. The extracts are washed with aqueous saturated sodium bicarbonate (50 ml), water, and then brine solution, dried over potassium carbonate, and concentrated to a solid. The solid is recrystallized from hexane-ethyl acetate to provide pure 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:13]3[CH:12]=[CH:11][N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[C:14]=3[N:15]=[CH:16][C:17]=2[N+:20]([O-:22])=[O:21])[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@@H]1CCN(Cc2ccccc2)C1
Yield: 88 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (2 g, 5.9 mmol), (R)-1-Benzyl-pyrrolidin-3-ylamine (2.4 g, 15.3 mmol), and diisopropylethylamine (6 mL, 35.4 mmol) in propan-2-ol (50 mL) was heated to reflux for 4 hours. Volatile components were removed under vacuum and the residue was purified by column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane), gave 2.48 g (88%) of (R)—N-(1-benzylpyrrolidin-3-yl)-5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine. LCMS (Method J, ESI): RT=0.98 min, M+H+=478.1; 1H NMR (400 MHz, CDCl3) δ: 9.29-9.27 (s, 1H), 9.10 (s, 1H), 8.20-8.17 (m, 2H), 7.63-7.57 (m, 2H), 7.53-7.49 (m, 2H), 7.36-7.25 (m, 6H), 6.77-6.76 (d, J=4.4, 1H), 4.55-4.54 (m, 1H), 3.73-3.63 (m, 1H), 2.94-2.91 (m, 1H), 2.78-2.77 (m, 2H), 2.49-2.41 (m, 4H), 1.90-1.88 (m, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[C:20]2[C@H:21]3[C@H:26]([CH2:27][CH2:28][C:19]=2[CH:18]=[CH:17][CH:16]=1)[NH:25][CH2:24][CH2:23][CH2:22]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:25]3[C@@H:26]4[C@H:21]([C:20]5[C:15]([O:14][CH3:13])=[CH:16][CH:17]=[CH:18][C:19]=5[CH2:28][CH2:27]4)[CH2:22][CH2:23][CH2:24]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1cccc2c1[C@@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1cccc2c1[C@@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 51 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 51% of theory; LC (method 2): tR=3.63 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=3)=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].B.O.O1CCCC1.S(=O)(=O)(O)O>O1CCCC1>[OH:27][CH2:26][CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:6]3[O:5][C:4]([N+:1]([O-:3])=[O:2])=[C:8]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:7]=3[CH:15]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)Cc1ccc(-c2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)cc1
Agent: B
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1oc2ccc(-c3ccc(CCO)cc3)cc2c1-c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 2 g. (0.00536 mole) of 4-(2-nitro-3-phenylbenzofuran-5-yl)phenylacetic acid (the product of step D of Example 1 hereof) in 100 ml. of tetrahydrofuran is cooled to 0° C. and 20 ml. of a borane solution in tetrahydrofuran is added while under a nitrogen atmosphere over 10 minutes. After warming to 20° C. the mixture is stirred for 16 hours. The solution is cooled to 0° C., 50 ml. of 1:1 water-tetrahydrofuran mixture and 15 ml. of 3N sulfuric acid are each added slowly and the mixture is stirred at 20° C. for 45 minutes. Evaporation provides a residue which crystallizes when triturated with hexane. Chromatography through silica gel in chloroform, eluting with chloroform, provides 5-[4-(2-hydroxyethyl)phenyl]-2-nitro-3-phenylbenzofuran, m.p. 86°-87° C.
Reaction SMILES: C(C(CCCC)COC(=O)CC[S:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:16]3[N:17]2[CH:20]=[N:21][N:22]=3)=[CH:12][CH:11]=1)C.N#N.CC(C)([O-])C.[K+].Br[CH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>CN(C=O)C.CCOC(C)=O.O>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][S:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][C:16]3[N:17]2[CH:20]=[N:21][N:22]=3)=[CH:12][CH:11]=1)[CH3:50]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: CC(C)(C)[O-]
Agent: N#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
11c (100 mg, 0.21 mmol) in DMF (1 mL) was degassed for 5 minutes with N2, and then cooled to 0° C. under N2. Potassium tert-butoxide (29 mg, 0.26 mmol) in DMF (1 mL) was degassed for 5 minutes with N2, and then added to the solution of 11c. The reaction was warmed to room temperature, and LCMS analysis showed no starting material remained after 10 minutes. Ethyl 4-bromobutyrate (0.04 mL, 0.24 mmol) was added, and the mixture was stirred for 20 minutes. The reaction was diluted with EtOAc and water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the desired product, 11d.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:23]2[CH:22]=[C:21]([C:24]#[C:25]C(C)(O)C)[CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][C:14]([C:30]#[C:31]C(C)(O)C)=[CH:15][CH:16]=2.[OH-].[Na+]>C1(C)C=CC=CC=1.CC(O)C>[C:30]([C:14]1[CH:15]=[CH:16][C:17]2[C:18]3[C:23](=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=3)[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH3:45])[C:12]=2[CH:13]=1)#[CH:31]
Reactant: COCCOCCOCCC1(CCOCCOCCOC)c2cc(C#CC(C)(C)O)ccc2-c2ccc(C#CC(C)(C)O)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C#Cc1ccc2c(c1)C(CCOCCOCCOC)(CCOCCOCCOC)c1cc(C#C)ccc1-2
Yield: 58.2 %

Procedure:
To a solution of 4,4′-[9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene-2,7-diyl]bis(2-methyl-3-butyn-2-ol) (0.363 g, 0.58 mmol) in 9 mL of toluene and 2 mL of i-PrOH, was added solid NaOH (0.15 g, 3.75 mmol). The mixture was heated under reflux for 1.5 h. After cooling, NaOH was filtered off and the solvents were evaporated and the residue was purified by column chromatography on silica gel (CH2Cl2/AcOEt 60:40) to yield 0.171 g (58%) of 2,7-diethynyl-9,9-bis[2-[2-(2-methoxyethoxy)ethoxy]ethyl]-9H-fluorene, mp 68° C.; 1H NMR (CDCl3) δ 2.37 (t, 4H, J=7.8 Hz), 2.74 (t, 4H, J=7.2 Hz), 3.17 (s, 2H), 3.20 (m, 4H), 3.35 (s, 6H), 3.39 (m, 4H), 3.54-3.47 (m, 8H), 7.50 (dd, 2H, J=7.8 Hz, J=1.3 Hz), 7.55 (d, 2H, J=1.3 Hz). 7.63 (d, 2H, J=7.8 Hz); 13C NMR (CDCl3) δ 39.5, 51.3, 59.1, 65.9, 66.8, 70.0, 70.4, 71.8, 77.9, 84.1, 120.1, 121.2, 127.0, 131.7, 140.2, 149.3. Anal. Calcd for C31H38O6 (506.63): C, 73.49; H, 7.56. Found: C, 73.59; H, 7.64.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[OH-].[Na+].CO.Cl>O1CCCC1.O>[Br:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[N:15]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=3[CH2:9][CH2:10][O:11][C:12]=2[CH:19]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 2 h

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester from Example 21 (518 mg) in tetrahydrofuran (10 ml) was added a solution of sodium hydroxide (117 mg) in water (2 mL). Methanol (5 mL) was also added to aid dissolution. After 2 hours, the reaction mixture was acidified with HCl (2M) and the reaction mixture was then extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo to yield 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccncc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
N'-t-butyl-N-benzoylhydrazine (1.0 g, 0.0052 mol) was suspended in 20 ml of toluene. Isonicotinoyl chloride hydrochloride (0.93 g, 0.0052 mol) was added and then a solution of sodium hydroxide (1.25 g of 50% aqueous NaOH) in 5 ml of water was added dropwise. After stirring at 23° C. for 2 hours, the solids were removed by filtration, washed with water and dried in air. The crude product was chromatographed on silica gel using 5% methanol/methylene chloride as eluant to afford pure N'-t-butyl-N-benzoyl-N'-isonicotinoylhydrazine. m.p. >210° C.
Reaction SMILES: [Cl:1][C:2]1[N:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[S:8])=[O:5].CN(C=O)C>C1COCC1>[ClH:1].[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:7]2[S:8][C:2]3[N:19]=[CH:18][CH:17]=[CH:16][C:3]=3[C:4](=[O:5])[N:6]=2)[CH:11]=1
Reactant: O=C(NC(=S)Nc1cccnc1)c1cccnc1Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: O=c1nc(Nc2cccnc2)sc2ncccc12
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 1.104 g (3.77 mmol) of 1-(2-chloronicotinoyl)-3-(3-pyridyl)thiourea and 10 ml of DMF was heated over a 140° C. oil bath. The mixture was stirred for 1 hour. The reaction mixture was allowed to cool, and then diluted with THF. The resulting crystal was collected by filtration, washed with THF, and then dried under reduced pressure to obtain to obtain 759 mg of 2-(3-pyridylamino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1ccc(N2CCN(C(=O)Nc3nc4cc(C)ccc4nc3OC)CC2)cc1
Yield: 80 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(4-methoxyphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 80%). 1H NMR (200 MHz, CDCl3): δ 2.48 (s, 3H), 3.16-3.14 (m, 4H), 3.78-3.82 (m, 6H), 4.13 (s, 4H), 6.84-7.02 (m, 4H), 7.14-7.33 (m, 3H), 7.53-7.64 (m, 1H).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@:22]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:23][CH:24]=O)=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:32])([CH3:31])[CH2:21][C@@:22]([C:26]([F:29])([F:28])[F:27])([OH:30])[CH2:23][C:24]#[CH:1])=[C:16]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:15]=1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C[C@@](O)(CC=O)C(F)(F)F)c1ccc(Cl)cc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#CC[C@](O)(CC(C)(C)c1ccc(Cl)cc1S(C)(=O)=O)C(F)(F)F
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a stirred solution of (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (12.5 g, 0.065 mol) and (R)-5-(4-chloro-2-methanesulfonylphenyl)-3-hydroxy-5-methyl-3-trifluoromethylhexanal (20.5 g, 0.054 mol) in 150 mL of dry MeOH was added potassium carbonate (13.8 g, 0.100 mol) at room temperature. The reaction was stirred overnight. The reaction was diluted with 200 mL of water and extracted with diethyl ether. The organic layers was washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. The crude material was eluted through a plug of silica using 20-25% diethyl ether/hexanes to provide (S)-6-(4-chloro-2-methanesulfonylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (18.5 g, 89%).
Reaction SMILES: [Cl-].C[Al+]C.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1.C([O:15][C:16]([C:18]1[CH:19]=[C:20]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[C:21]2[CH:25]=[CH:24][S:23][C:22]=2[CH:26]=1)=O)C>ClC(Cl)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:16]([C:18]2[CH:19]=[C:20]([O:27][C:28]3[CH:29]=[CH:30][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:32][CH:33]=3)[C:21]3[CH:25]=[CH:24][S:23][C:22]=3[CH:26]=2)=[O:15])=[N:7][CH:8]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2ccsc2c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3ccsc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
Dimethylaluminum chloride (15.5 mmol, 15.5 ml of 1M in hexanes) was added to a solution of 2-amino-5-picoline (1.67g, 15.5 mmol) in dichloroethane (10 ml) at 0 C. The mixture was allowed to warm to room temperature, held 30 minutes at room temperature, then recooled to 0° C. and treated with 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid ethyl ester (0.58 g, crude product from previous step) in dichloroethane (5 ml). The mixture is allowed to warm to room temperature and held at room temperature for 8 h. The reaction was quenched by the drop wise addition of MeOH (2 mL) at 0 C, followed by 1M aqueous pH6 phosphate buffer (10 ml), then ethyl acetate (50 ml). Separation of the organic layer followed by evaporation yielded crude product (1.1 g). This was purified by silica gel chromatography (0-20% MeOH/CHCl3) to yield 0.35 g (59%) of 4-(4-methanesulfonyl-phenoxy)-benzo[b]thiophene-6-carboxylic acid (5-methyl-pyridin-2-yl)-amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.85(s, 1H), 8.69 (s, 1H), 8.22(d, J=8.8, 2H), 8.10 (d, J=8.6, 1H), 8.03 (d, J=5.5, 1H), 7.94 (d, J=8.8, 2H), 7.76 (d, J=1.3, 1H), 7.67 (dd, J=9.0, 2.0, 1H), 7.38 (d, J=5.5, 1H), 7.26 (d, J=8.8, 2H), 3.21 (s, 3H0, 2.28 (s, 3H). LRMS for C22H18N2O4S2 m/z 439 (M+H)+. Anal. Calcd. for C22H18N2O4S2 C, 60.26;H, 4.14; N, 6.39; Found: C, 60.58; H, 4.23; N, 6.22.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2].[S:28](Cl)([Cl:31])(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:28]([Cl:31])(=[O:30])=[O:29])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:27])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[N:12]2[N:11]=1)[CH3:2]
Reactant: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Reactant: O=S(=O)(Cl)Cl
Product: CCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 0.3 g (0.81 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-heptyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 22A). This gives 0.3 g (78.9%) of sulphonyl chloride as a white foam which is directly reacted further.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:18])[CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl/[CH:20]=[CH:21]\Cl.[C:23](=[S:25])=[S:24]>CS(C)=O.[OH-].[K+]>[S:24]1[CH:21]=[CH:20][S:25][C:23]1=[C:11]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:18])[C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13]
Reactant: CC(C)OC(=O)CC(=O)c1ccc2c(c1)OCO2
Reactant: Cl/C=C\Cl
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)OC(=O)C(C(=O)c1ccc2c(c1)OCO2)=C1SC=CS1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropyl 3-(1,3-benzodioxol-5-yl)-3-oxopropionate (2.5 g) was dissolved in 30 ml of DMSO, to which 2.2 ml of 10N potassium hydroxide and 0.7 ml of carbon disulfide were added under ice cooling. The temperature of the resulting mixture was allowed to rise to room temperature, at which the mixture was stirred for 1 hour. The reaction mixture then turned to a reddish clear solution. After the reaction mixture was ice-cooled again, 1.066 g of cis-1,2-dichloroethylene were added, the temperature of the resultant mixture was allowed to rise to room temperature, followed by stirring for 3 hours. When the solution was poured into ice water, crystals precipitated. Those crude crystals were recrystallized from benzene-hexane, whereby 385 mg of isopropyl 2-(1,3-dithiol-2-ylidene)-3-[3,4-(methylenedioxy)phenyl]-3-oxopropionate were obtained as reddish crystals (yield: 11%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][Si:14]([C:17]#[C:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:16])[CH3:15]
Reactant: COC(=O)Cc1ccccc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl 2-(2-iodophenyl)acetate (I9) (4.65 g, 16.8 mmol), PdCl2(PPh3)2 (295 mg, 421 μmol) and Cu(I)I (80.0 mg, 421 μmol) were placed into an oven dried reaction flask under nitrogen. (Trimethylsilyl)acetylene (2.80 mL, 20.2 mmol), dry degassed THF (20 mL) and triethylamine (20 mL) were added and the reaction mixture was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give a black residue which was adsorbed onto silica then chromatographed on silica gel (0-5% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I10) (4.63 g, 99%) as a light brown liquid; 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J=7.5, 0.8 Hz, 1H), 7.32-7.14 (m, 3H), 3.84 (s, 2H), 3.71 (s, 3H), 0.26 (s, 9H). LCMS Method C: rt 6.64 min.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:3]([OH:16])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].N1C=CC=CC=1.[Si:30](Cl)([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[NH2:1][C@@H:2]([CH2:17][CH:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C@H:3]([O:16][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH2:4][N:5]([CH3:15])[C:6](=[O:14])[O:7][CH2:8][CH2:9][Si:10]([CH3:12])([CH3:13])[CH3:11]
Reactant: CN(C[C@@H](O)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN(C[C@@H](O[Si](C)(C)C)[C@@H](N)CC1CCOCC1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A 100 mL flask was charged with 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-2-hydroxy-4-(tetrahydro-2H-pyran-4-yl)butyl(methyl)carbamate (100 mg, 0.29 mmol) dissolved in THF (10 mL), pyridine (68 mg, 0.87 mmol) was added at 0° C. Me3SiCl (94 mg, 0.87 mmol) was added and the mixture was stirred for 2 h at rt. The mixture was quenched with 1% aq HCl and extracted with EtOAc (3×15 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to give 2-(trimethylsilyl)ethyl (2R,3S)-3-amino-4-(tetrahydro-2H-pyran-4-yl)-2-(trimethylsilyloxy)butyl(methyl)carbamate (110 mg, 92%)
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[CH2:22]([Br:25])[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:24][C:23]#[CH:22])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[Br:25][CH2:22][C:23]1[CH:6]=[CH:7][C:8]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:24]=1
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCc1ccc2ccccc2c1
Product: C#CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1

Procedure:
In an analogous manner to that described in Example 44(e), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate [Example 46(b)] with propargyl bromide in the presence of potassium carbonate in acetone there was obtained tert-butyl (3RS,4RS)-3-hydroxy-4-(4-prop-2-ynyloxy-phenyl)-piperidine-1-carboxylate, alkylation of which with 2-bromomethylnaphthalene in analogy to Example 1(g) gave tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-(4-prop-2-ynyloxy-phenyl)-piperidine-1-carboxylate as a pale yellow solid; MS: 472 (M+H)+.
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][C:13]1[C:14]([O:28][CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:15][C:16]([NH:19][C:20]2[CH:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=2)=[N:17][CH:18]=1.[CH3:43][N:44]([CH3:49])[CH2:45][C:46](O)=[O:47].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[C:26]([C:23]1[N:24]=[CH:25][C:20]([NH:19][C:16]2[CH:15]=[C:14]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[C:13]([NH:12][C:46](=[O:47])[CH2:45][N:44]([CH3:49])[CH3:43])=[CH:18][N:17]=2)=[N:21][CH:22]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)Nc1cnc(Nc2cnc(C#N)cn2)cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.2 %

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide (95 mg, 0.49 mmol) was added to a solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (140 mg, 0.33 mmol), N,N-dimethylglycine (51 mg, 0.49 mmol), 1-hydroxybenzotriazole hydrate (76 mg, 0.49 mmol) and N-ethyldiisopropylamine (86 μL, 0.49 mmol) in DMF (4 mL). The mixture was stirred overnight at room temperature then partitioned between ethyl acetate and water. The organic phase was washed sequentially with water, dilute sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated. Preparative HPLC gave tert-butyl 4-((2-(5-cyanopyrazin-2-ylamino)-5-(2-(dimethylamino)acetamido)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (24 mg, 14%) as an off-white powder.