Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([OH:25])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].Cl[CH2:27][O:28][CH2:29][CH3:30].C(N(C(C)C)CC)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:27][O:28][CH2:29][CH3:30])[CH:12]=[CH:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOCCl
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)C=C[C@]32O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C

Procedure:
A solution of 9.20 g of 3β-acetoxy-14β-hydroxyandrosta-5,15-dien-17-one (G. Groszek et al., Bull. Pol. Acad. Sci., Chem., 34, 1986, 313), 11 ml of ethyl chloromethyl ether, 54 ml of diisopropylethylamine in 750 ml of dichloromethane was heated at reflux for 24 hrs. The solution was then cooled and poured into 500 ml of aq. 8% citric acid solution. The lower layer was separated, washed with water, dried over sodium sulfate and avaporated to dryness. The crude product was purified by chromatography using cyclohexane/chloroform/acetone 80/10/10 as eluant to give 6.10 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5,15-dien-17-one as a white solid.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([Cl:26])[C:14]=1[C:15](O)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([Cl:26])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Product: O=C(N[C@@H]1CCC[C@@H]1N1CCCC1)c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The title compound, white solid, MS: m/e=395.1 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dichloro-4-trifluoromethyl-benzoic acid (intermediate Y).
Reaction SMILES: O1C2C=CC=CC=2OC[CH:2]1CN1CCCC(COC)(C)C1.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH:23]1[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C:35]([C:40]([OH:43])([CH3:42])[CH3:41])([CH3:39])[CH2:34]1>>[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH2:24][CH:23]1[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C:35]([C:40]([O:43][CH3:2])([CH3:42])[CH3:41])([CH3:39])[CH2:34]1
Reactant: CC(C)(O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Reactant: COCC1(C)CCCN(CC2COc3ccccc3O2)C1
Product: COC(C)(C)C1(C)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methoxymethyl-3-methylpiperidine except that 2-[1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]propan-2-ol was used instead of [1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidin-3-yl]methanol.
Reaction SMILES: [C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([C:11]#[CH:12])=[CH:7][CH2:6]1)#[N:2].ClC1C=CC=C(C(OO)=[O:29])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]([C:19]#[N:20])([CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:4][CH:5]1[CH2:10][CH2:9][C:8]2([O:29][CH:7]2[CH2:6]1)[C:11]#[CH:12])#[N:2]
Reactant: C#CC1=CCC(CC(C#N)(C#N)CCC(F)(F)F)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: C#CC12CCC(CC(C#N)(C#N)CCC(F)(F)F)CC1O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.1 %

Procedure:
To a solution of 0.31 g of 4-(2,2-dicyano-5,5,5-trifluoropentyl)-1-ethynylcyclohexene in 3 mL of chloroform was added 0.23 g of m-chloroperbenzoic acid at 0° C., followed by stirring at room temperature for 5 hours. After the reaction mixture was cooled to 0° C., 5 mL of a 10% aqueous sodium sulfite solution was added thereto, followed by extraction twice with 30 mL of chloroform. The combined organic layer was washed sequentially with 30 mL of a 10% aqueous sodium sulfite solution, 30 mL of a saturated aqueous sodium hydrogen carbonate solution and 30 mL of a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.22 g of 4-(2,2-dicyano-5,5,5-trifluoropentyl)-1,2-epoxy-1-ethynylcyclohexane (hereinafter referred to as the present compound (4)) represented by the following formula:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([NH2:14])[C:9]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].[C:22]([C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].[OH-:36].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([CH3:13])[N:11]=[C:10]([N:14]([S:32]([C:29]2[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)(=[O:33])=[O:36])[S:32]([C:29]2[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[C:9]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCCOc1c(-c2ccc(C)cc2)c(N)nn1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)OCCOc1c(-c2ccc(C)cc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)nn1C
Yield: 10.4 %

Procedure:
To 2-{[3-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]oxy}ethyl acetate (Preparation 24) (155 mg) in dichloromethane (20 ml) at room temperature was added 4-tert-butylbenzenesulfonyl chloride (374 mg), tetrabutylammonium hydrogen sulfate (45 mg) and potassium hydroxide (374 mg) and then the mixture was sonicated for 5.25 hrs. The reaction was diluted with dichloromethane (100 ml) and washed with water (3×100 ml) and brine (100 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 10 g) eluted with dichloromethane:hexane (4:1) to yield the title compound as a white solid (38 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([N:21]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]1=2.[CH2:36]([Sn](CCCC)(CCCC)C=C)[CH2:37]CC>CN(C=O)C.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>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:21]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:18]([C:15]2[CH:16]=[CH:17][C:9]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:36]=[CH2:37])[CH2:13][CH2:12][O:11][C:10]=3[CH:14]=2)(=[O:20])=[O:19])=[CH:29][CH:30]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Yield: 55 %

Procedure:
A mixture of 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (1.2 g, 2.626 mmol), tributyl(vinyl)stannane (3.0 g, 10.5 mmol, Finar), Pd(PPh3)4 (303 mg, 0.131 mmol) in DMF (15 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave irradiation for 2 h at 100° C. After completion, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by combi flash column chromatography (column size: 12 g; elution: 0-5% ethyl acetate in hexane) to get N-(4-methoxybenzyl)-N-(thiazol-2-yl)-4-(2-vinylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (750 mg, 68.0%) as a yellow solid. m/z (ESI) 520.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[C:26]([CH3:27])=[C:25]([CH3:28])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.[BH4-].[Na+].O>CO>[CH3:18][CH:19]1[CH2:24][CH2:23][CH:22]([NH:25][CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cc2)c1
Reactant: CC1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1CCC(NCc2ccc(-c3cccc(C(N)=O)c3)cc2)CC1
Reaction time: 16 h

Procedure:
To a solution of 4′-formylbiphenyl-3-carboxylic acid amide (700 mg, 3.1 mmol) in methanol (15 mL) was added 4 Å molecular sieves (700 mg) and 4-methylcyclohexylamine (421 mg, 3.7 mmol). The mixture was stirred for 16 h before adding sodium borohydride (588 mg, 15.5 mmol). After 1 h water (10 mL) was added, the mixture was filtered through celite and the solvent removed in vacuo. Purification of the residue by column chromatography (0.5% NH3: 6% MeOH: DCM) gave the title compound: RT=2.53 min; m/z (ES+)=323.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:23]5[CH2:22][CH:21]([CH3:20])[NH:26][CH:25]([CH3:27])[CH2:24]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93.1 mg (73%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.75 (br s, 1H, NH), 9.23 (br s, 1H), 8.32 (s, 1H), 7.73 (dd, J=2.6 & 6.7 Hz, 1H), 7.41 (m, 1H), 7.33-7.38 (m, 2H), 6.57 (d, J=2 Hz, 1H), 4.22 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.52 (m, 2H, 2×CH), 2.22 (s, 3H, CH3), 0.99 (d, J=6 Hz, 6H, 2×CH3), 0.98 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:12][C:4]1[CH:3]=[C:2]([CH2:20][CH2:19][C:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:21])[CH:7]=[CH:6][C:5]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: C=CC(O)C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(CCC(=O)C2CCCC2)cc1Cl
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 4-bromo-2-chloro-1-methanesulfonyl-benzene (1.5 g, 5.6 mmol), 1-cyclopentyl-2-propen-1-ol (0.88 g, 6.96 mmol) and sodium acetate (0.57 g, 6.9 mmol) in DMAC (20 mL) was purged with N2 for 30 mins. Palladium (II) acetate (25 mg, 0.11 mmol) was added and the mixture was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1 N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the desired product (1.2 g, 69%). 1H NMR (300 MHz, CDCl3): δ 1.56-1.85 (br m, 8H), 2.83 (m, 3H), 2.96 (t, J=7.5 Hz, 2H), 3.25 (s, 3H), 7.29 (dd, J=8.1, 1.5 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:17])[C:12]([O:14]CC)=[O:13].ClC1C=CC=C(Cl)C=1NC1C=CC=CC=1C(O)C(OC)=O>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:17])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Product: O=C(O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Yield: 77.7 %

Procedure:
The same procedures as in the Step 4 of Example 1 were repeated except that 13.6 g of ethyl 2-(2,6-dichloroanilino)-phenylglycolate were employed instead of 13.0 g of methyl 2-(2,6-dichloroanilino)phenylglycolate, thereby yielding 9.7 g of 2-(2,6-dichloroanilino)phenylglycolic acid. m.p. 139°-141.5° C. Yield: 78% of theoretical amount
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:13][OH:14]>N1C=CC=CC=1>[C:1]([O:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CO
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)COC(=O)CCc1ccccc1

Procedure:
33.7 g (0.2 mole) of hydrocinnamoyl chloride was added to a stirred solution of 18 g (0.2 mole) of ethyl glycolate in 20 ml of pyridine. The precipitated pyridine hydrochloride was filtered, washed with benzene, and discarded. The benzene solution of carboethoxymethyl hydrocinnamate was water washed, dried over sodium sulfate, and the solvent stripped off using a rotary evaporator. The yield of product was essentially quantitative. Its structure was established by infrared and nuclear magnetic resonance spectroscopy. It had n30D 1.4900 and d304 1.0919.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=1.[CH2:13]([CH2:17][C:18](=O)[CH3:19])[C:14]([CH3:16])=O>>[CH3:19][C:18]1[N:1]([CH2:2][CH2:3][CH2:4][C:5]2[S:9][C:8]([C:10]([NH2:12])=[O:11])=[CH:7][CH:6]=2)[C:14]([CH3:16])=[CH:13][CH:17]=1
Reactant: NCCCc1ccc(C(N)=O)s1
Reactant: CC(=O)CCC(C)=O
Product: Cc1ccc(C)n1CCCc1ccc(C(N)=O)s1

Procedure:
5-(3-Aminopropyl)-2-thiophenecarboxamide is reacted with acetonylacetone to give 5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide, m.p. 144°-146° C. (see J. Chem. Soc. Chem. Commun. 800 [1982]). This is alkylated with n-butyl bromide to give N-butyl-5-[3-(2,5-dimethylpyrrol-1-yl)propyl]-2-thiophenecarboxamide (see Synthesis 266 [1976]). The latter is cleaved with hydroxylamine hydrochloride to give 5-(3-aminopropyl)-N-butyl-2-thiophenecarboxamide.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([OH:18])=O)=[C:4]2[CH:3]=[CH:2]1.[N:19]([CH2:22][C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:24])=[N+:20]=[N-:21].CCN(C(C)C)C(C)C.O>CN(C=O)C>[N:19]([CH2:22][C@@H:23]([NH:24][C:16]([C:12]1[S:13][CH:14]=[CH:15][C:11]=1[NH:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12)=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H](NC(=O)c1sccc1Nc1ccnc2[nH]ccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 3-(1H-pyrrolo[2,3-b]pyridin-4-ylamino)thiophene-2-carboxylic acid (130.00 mg; 0.50 mmol; 1.00 eq.), (1S)-2-azido-1-phenylethanamine (129.67 mg; 0.55 mmol; 1.10 eq.), n,n-diisopropylethylamine (0.33 ml; 2.01 mmol; 4.00 eq.) in DMF (2.00 ml), O-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluoro-phosphate (209.70 mg; 0.55 mmol; 1.10 eq.) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water. The solid was too tiny to be filtered. The aqueous mixture was extracted with ethyl acetate to afford the title compound in 79% yield. LCMS: m/e 404 (M+H). 1H NMR (DMSO-d6): ppm 11.56 (1H, br, s.), 10.25 (1H, s.), 8.72 (1H, d, J=8.44 Hz), 8.02 (1H, d, J=5.48 Hz), 7.85 (1H, d, J=5.52 Hz), 7.50 (1H, d, J=5.48 Hz), 7.42-7.44 (1H, m), 7.26-7.35 (4H, m), 6.81 (1H, d, J=5.16 Hz), 6.40 (1H, dd, J=3.28, 1.84 Hz), 5.27-5.32 (1H, m), 3.79 (1H, dd, J=12.84, 9.52 Hz), 3.60 (1H, dd, J=12.48, 4.76 Hz).
Reaction SMILES: [C:1]1([CH3:28])[C:2]([C:7]([C@:9]([C:25]([OH:27])=[O:26])([OH:24])[C@:10]([C:15]([C:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])([OH:14])[C:11]([OH:13])=[O:12])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.CO.[CH3:31][O:32][C:33]([C@@H:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@@H:36]1[NH:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]>CC(C)=O>[C:1]1([CH3:28])[C:2]([C:7]([C@:9]([C:25]([O-:27])=[O:26])([OH:24])[C@:10]([C:15]([C:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])([OH:14])[C:11]([O-:13])=[O:12])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:31][O:32][C:33]([C@H:35]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@@H:36]1[NH:41][CH2:40][CH2:39][CH2:38][CH2:37]1)=[O:34]
Reactant: COC(=O)[C@@H](c1ccccc1)[C@H]1CCCCN1
Reactant: Cc1ccccc1C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c1ccccc1C
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)[C@H](c1ccccc1)[C@H]1CCCCN1
Product: Cc1ccccc1C(=O)[C@@](O)(C(=O)[O-])[C@](O)(C(=O)[O-])C(=O)c1ccccc1C
Reaction time: 17 h
Yield: 121.5 %

Procedure:
Ditoluoyl-D-tartaric acid (5.033 g, 12.4 mmol) was suspended in a solution of 2% methanol in acetone (10 ml), and a solution of threo-methylphenidate (2.9 g, 12.4 mmol) in the same solvent (10 ml) was added. The solution was gently warmed to reflux whereupon all the reagents dissolved. The solution was immediately cooled and crystals began to form. The solution was allowed to stand at 4° C. for 17 hours and was then filtered. The crystals were washed with acetone (3×15 ml) and dried in vacuo to yield the ditoluoyl-D-tartrate salt of d-threo methylphenidate (3.516 g, 44.3% by weight; corresponding to 97% ee d-threo methylphenidate, as determined by chiral HPLC after salt cracking). The mother liquors were dried in vacuo to yield ditoluoyl-D-tartrate salt of l-threo-methylphenidate as a solid, dry form (4.508 g, 50.5% yield, 88% ee).
Reaction SMILES: B1(C)[O:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H]2N1CCC2>C1(C)C=CC=CC=1.C(Cl)Cl.C1COCC1>[CH:20]1([CH2:15][C@@H:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O[C@@H](CC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A solution of 2.7 mL of 1.0 M (R)-2-methyl-CBS-oxazaborolidine solution in toluene in 4 mL of CH2Cl2 at −25° C. was treated with 1.4 mL of 2.0 M borane methyl sulfide complex in THF and stirred cold for 10 min. A solution of 501 mg (2.66 mmol) of cyclopentylmethylene phenyl ketone (from Step B) in 2 mL of CH2Cl2 was added over 25 min and the resulting mixture was stirred cold for an additional 45 min. The reaction was quenched by pouring it into cold (−25° C.) MeOH. The quenched reaction was warmed to rt and stirred for 45 min until gas evolution ceased. The mixture was concentrated and the residue dissolved in 20 mL of MeOH and concentrated again. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 413 mg (81%) of the title compound: RF: 0.53 (4:1 v/v hexanes/ EtOAc); 1H NMR (300 MHz): δ 1.10-1.17 (m, 2H), 1.47-1.89 (m, 9H), 4.69 (m, 1H), 7.25-7.35 (m, 5H).
Reaction SMILES: [F-].[Cs+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([SH:13])=[N:9][CH:10]=[CH:11][CH:12]=1.CS(O[C@H:19]([CH3:38])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=[O:21])(=O)=O.Cl>CN(C=O)C.O>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([C:20](=[O:21])[C@@H:19]([S:13][C:8]3[C:7]([O:6][CH2:5][O:4][CH3:3])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH3:38])=[CH:23][CH:24]=2)=[CH:31][CH:32]=1
Reactant: COCOc1cccnc1S
Reactant: COc1ccc(COc2ccc(C(=O)[C@@H](C)OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cccnc1S[C@@H](C)C(=O)c1ccc(OCc2ccc(OC)cc2)cc1

Procedure:
Dried cesium fluoride (5.31 g, 35.0 mmol) and 3-(methoxymethoxy)pyridine-2-thiol (6.0 g, 35.0 mmol) synthesized in Reference Example 15 were dissolved in DMF (120 mL), and under stirring with cooling with ice, (1R*)-2-{4-[(4-methoxybenzyl)oxy]phenyl}-1-methyl-2-oxoethyl methanesulfonate (11.58 g, 31.8 mmol) synthesized in the above (4) was added. The reaction solution was stirred for 20 hours with cooling with ice, then 2 N HCl (20 mL) and water (180 mL) were added, and further stirred for 20 minutes with cooling with ice. The formed solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the entitled compound (13.3 g, containing 20% side product) as a milky white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([O:18]CC)=[O:17])=[CH:13][C:14](=[O:15])[C:3]1=2>[OH-].[Na+]>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][C:14](=[O:15])[C:3]1=2
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2ccccc2c2oc(C(=O)O)cc(=O)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5.40 g (0.020 mole) of ethyl 4,5-dihydro-5-methyl-4-oxopyrano [3,2-b]indole-2-carboxylate in 80 ml of 1% aqueous sodium hydroxide was stirred at room temperature for 30 min. The nearly one-phase mixture was extracted twice with 50 ml CH2Cl2 and the aqueous layer was cooled in ice and acidified with 4 N HCl. The gelatinous yellow crude product was filtered, digested for a few minutes on a steam bath with 100 ml hot water and then re-filtered. Recrystallization from ab. EtOH gave yellow needles of mpt. 280°-dec.