Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.4 g, 2.5 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (6 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′S)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a light yellow solid (1.5 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:6]([CH2:8][C:9]#[N:10])=O.O.[NH2:17][NH2:18]>C(O)C>[NH2:10][C:9]1[CH:8]=[C:6]([C:5]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:18][N:17]=1
Reactant: COc1ccc(C(=O)CC#N)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc(N)n[nH]2)cc1OC

Procedure:
3,4-Dimethoxybenzoylacetonitrile (3.6 g) was dissolved in ethanol (20 ml), to which was subsequently added hydrazine monohydrate (0.87 ml) under cooling with ice. The mixture was heated under ref lux for 7 hours, allowed to cool and then the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate to obtain the title compound (2.92 g) as colorless crystals (melting point: 124-125° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Oc2ncccn2)cc1
Reactant: O=S(Cl)Cl
Product: ClCc1ccc(Oc2ncccn2)cc1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted alcohol, for example, the known compound (4-pyrimidin-2-yloxyphenyl)methan-1-ol, is halogenated with, for example thionyl chloride, to afford the corresponding 2-[4-(chloromethyl)phenoxy]pyrimidine (A). Intermediate (A) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-one (B). A mixture of intermediate (B) and an appropriately substituted haloalkyl derivative, for example bis(trifluoromethoxyphenyl)bromomethane, is reacted in the presence of n-butyl lithium, to afford the corresponding 4-{bis[4-(trifluoromethoxy)phenyl]methyl}-1-[(4-pyrimidin-2-yloxyphenyl)methyl]piperidin-4-ol (I-A). Intermediate (I-A) is then oxidized, with for example hydrogen peroxide, in an appropriate solvent, to form an N-oxide, a compound of formula I-C. In a separate synthesis, intermediate (I-A) is reacted with a thiohalide, for example (dimethylamino)sulfur trifluoride, to provide halogen-derived compounds of formula I-D, wherein X is, for example fluorine. Examples 1 and 3, set forth below, provide detailed methods to how compounds of formula I (-A, -C and -D) shown in Scheme 1 were prepared.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:39]=[CH:38][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([N:12]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:13][C@H:14]([O:23][Si:24]([CH2:29][CH3:30])([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[O:16]([CH2:15][C@@H:14]([O:23][Si:24]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:29][CH3:30])[CH2:13][N:12]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH:10]1[CH2:9][CH2:8][CH2:7][C:6]2[CH:38]=[CH:39][C:3]([CH2:2][O:1][S:48]([CH3:47])(=[O:50])=[O:49])=[CH:4][C:5]=2[CH2:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(CO)cc2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](COc1ccccc1)CN(C(=O)OC(C)(C)C)C1CCCc2ccc(COS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of N-(3-hydroxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)-N-[(2S)-3-phenoxy-2-(triethylsilyl-oxy)propyl]-tert-butoxycarbonylamine (1.93 g) and triethylamine (0.58 ml) in dichloromethane (40 ml) was added dropwise methanesulfonyl chloride (0.27 ml) under ice-cooling. After stirring at room temperature for 6 hours, the reaction mixture was washed successively with water, sodium bicarbonate solution, water and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo to afford crude N-[(2S)-3-phenoxy-2-(triethylsilyloxy)propyl]-N-(3-methylsulfonyloxymethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-tert-butoxycarbonylamine (2.18 g), which was used without purification.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][C:17]=1[CH3:18])(=[O:11])[CH3:10].C(Cl)(Cl)(Cl)Cl>C(O)C>[C:9]([C:12]1[C:13]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][C:15]([NH:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[C:16]([Br:1])[C:17]=1[CH3:18])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)c1c(C)cc(NC(C)(C)C)nc1NC(C)(C)C
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1c(NC(C)(C)C)nc(NC(C)(C)C)c(Br)c1C
Reaction time: 8 h

Procedure:
534 mg. (3 mmol.) of N-bromosuccinimide (recrystallized from water) were added in small portions to a solution of 831 mg. (3 mmol.) of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine (Compound V) in 20 ml. of carbon tetrachloride and 5 ml. of ethanol, and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was evaporated down at reduced pressure, and the residue was partitioned between ether and water. The organic phase was dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain yellow crystals. Recrystallization from methanol/water gave the product (990 mg.), m.p. 99°-100° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:18][O:19]C)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:11]([N:8]1[CH2:9][CH2:10][C:6]([CH2:18][OH:19])([CH2:4][O:3][CH3:1])[CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(COC)CCN(Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCC1(CO)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
A solution of 1-benzyl-3-methoxymethylpyrrolidine-3-carboxylic acid ethyl ester (Example A18a, 2.30 g, 8.3 mmol) in anhydrous tetrahydrofuran (10 mL) is added dropwise to an ice-cold suspension of lithium aluminum hydride (0.821 g, 22 mmol) in tetrahydrofuran (50 mL). The resulting mixture is stirred at room temperature for 18 hours, cooled and quenched by the sequential dropwise addition of 1N sodium hydroxide and water. The solids are removed by filtration, re-suspended in hot tetrahydrofuran and filtered. The combined filtrates are concentrated in vacuo and the residue is partitioned between dichloromethane and water. The organic extracts are dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (1.71 g). 1N NMR (200 MHz, CDCl3): δ 7.41–7.17 (m, 5H), 3.84–3.43 (m, 4H), 3.34 (s, 2H), 3.32 (s, 3H), 2.85–2.60 (m, 2H), 2.54–2.14 (m, 3H), 1.98–1.50 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[CH:14]=1)=[CH:11][C:10]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[C:9]([CH3:21])[C:8]=2[CH3:22])=[O:4].[OH-].[K+].O>CO>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH3:22])[C:9]=1[CH3:21])[NH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:14][C:13]2=[O:15])(=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OC)[nH]c2c(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=O)c1cc2c(=O)cc(C(=O)O)[nH]c2c(C)c1C

Procedure:
6.1 g of 6-butyryl-7,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid methyl ester are heated under reflux for 4 hours together with 3.66 g of potassium hydroxide, 1.46 ml of water and 64.4 ml of methanol. The reaction mixture is concentrated to dryness by evaporation, partitioned between ethyl acetate and water, the aqueous phases are acidified and the precipitated crystals are filtered with suction and washed with water. The 6-butyryl-7,8-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid obtained in this manner melts at 267°-269° after recrystallisation from methanol/ethanol.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([Cl:13])=[CH:11][C:10]([F:14])=[C:9]([C:15]3[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[Cl:13][C:12]1[C:6]2[O:5][C:4]([C:1]([O:3][CH2:32][CH3:33])=[O:2])=[CH:8][C:7]=2[C:9]([C:15]2[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)=[C:10]([F:14])[CH:11]=1
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 99 %

Procedure:
0.08 g (0.21 mmol) of 3-(2-carboxy-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of ethanol, and 4.0 mg (0.04 mmol) of sulfuric acid was added thereto, followed by refluxing for 2 hours. Ethanol was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with diethyl ether. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.09 g (yield: 99%) of the desired product. Melting point: 118-120° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:32]=C)[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1.I([O-])(=O)(=O)=[O:35].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:32]=[O:35])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: C=Cc1nc2c(N)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2c1nc(C=O)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.6 %

Procedure:
In a mixed solution of 4 mL of tetrahydrofuran and 1 mL of water, 20 mg (0.04 mmol) of 1-[4-(6-amino-8-vinyl-purin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)-urea was dissolved, and 20 μL of a 0.1 M osmium tetraoxide aqueous solution and 40 mg (0.19 mmol) of sodium periodate were added thereto and the mixture solution was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and purified by a silica gel column (dichloromethane:methanol=9:1) to obtain 18 mg (90%) of a target product as a white crystal.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(C(C)C)C(C)C)C.[Cl:23][C:24]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:25]=1[O:26][C:27]1[C:32]([C:33](N2C3C(=CC=CC=3)NCC2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1>C(O)C.[Pd]>[Cl:23][C:24]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:25]=1[O:26][C:27]1[C:32]([C:33]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH2:1][CH2:2][CH2:3][CH:4]3[CH2:13]2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: c1ccc2c(c1)NCc1cccn1-2
Agent: [Pd]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CC2CCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 4,5-dihydro-pyrrolo[1,2-α]quinoxaline (30.6 mg, 0.18 mmol, 1.2 equiv; [CAS RN 56721-86-9]) in ethanol (5 mL) was added palladium on carbon (3.2 mg, 0.003 mmol, 0.02 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (3 bar) at rt for 4 h. The reaction mixture was concentrated under reduced pressure, filtered over Celite® and the remaining residue redissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (64 mg, 86 μL, 0.50 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 2-(2,5-dichloro-phenoxy)-nicotinoylchloride (45.4 mg, 0.15 mmol, 1.0 equiv; prepared according to Example 122) and the reaction mixture stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 21.4 mg (32%) of the title compound. MS (ISP): 440.1 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[N+:14]([C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:9])[O:8][C:1](=[O:2])[CH2:4]2)([O-:16])=[O:15]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)O1
Yield: 87.9 %

Procedure:
A mixture of 2 carboxymethyl-4-nitro-benzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (30 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (3a) in Scheme 2) as a yellow solid (10.51 g, 88%). Borane tetrahydrofuran complex (35.6 mL, 1M in THF) was added dropwise over 40 min to a solution of 6nitro-isochroman-1,3-dione (2 g, 9.66 mmol) in THF (40 mL) at 0° C. The contents were stirred for 18 hrs at 25° C., cooled to 0° C., quenched with methanol (30 mL), and stirred for 1 hr. The solvents were removed under vacuum, ethyl acetate (30 mL) added and the organic phase washed with 10% aqueous hydrochloric acid. The aqueous acidic layer was reextracted with ethyl acetate (30 mL), the combined organic layers dried with magnesium sulfate, and evaporated under vacuum until 2 mL of ethyl acetate remained. This solution was filtered through silica gel washing with methylene chloride (30 mL) to remove impurities. The silica gel was flushed with ethyl acetate, solvent removed under vacuum to give a solid which was slurryed in methylene chloride and filtered to afford the diol as a white solid, 1.38 g, 73%.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH:19][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3ccccc3)c1)N2
Yield: 59 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and benzenesulfonylchloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 20 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether:ethyl acetate=15:1) to afford 120 mg of N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 59%). MS (ESI+APCI) M+1=407.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1.[OH:11]O>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:11]
Reactant: OO
Reactant: COCCSc1nc[nH]n1
Agent: [Pd]
Solvent: CC(=O)O
Product: COCCS(=O)c1nc[nH]n1

Procedure:
A solution of 31.8 g. of 3-(2-methoxyethylthio)-1,2,4-triazole was dissolved in 300 ml. of acetic acid and heated to 80° C. To this solution was added by portions 67.2 ml. of 100 vol. hydrogen peroxide and the temperature was maintained at 80° C. for two hours with cooling as necessary in the early stages. A small amount of 10% palladium/charcoal catalyst was added to destroy excess hydrogen peroxide. After an hour the solution was filtered and sulphur dioxide passed through the mixture as a precaution in case peroxides had been formed. The solution was vacuum evaporated and crystals of the sulphonyl compound were removed. On the addition of further petroleum ether to the liquors, filtration and vacuum distillation, there was obtained an oily liquid, 3-(2-methoxyethylsulphinyl)-1,2,4-triazole. Elemental analysis satisfactory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1COCC1.[Na]>CO>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:1][C:2]2[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ncccc1CO
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2CO)CC1

Procedure:
The product from Step 1 and 1-(tert-butyloxycarbonyl)piperidin-4-one are heated together in a solvent such as THF or methanol. The cooled mixture is treated with sodium cyanpborohydride to give 1-(tert-butyloxycarbonyl)-4-(3-hydroxymethyl-2-pyridylamino) piperidine.
Reaction SMILES: [CH2:1]1[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]([NH2:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>>[CH2:16]([NH:17][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH:18][CH2:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NCCCCCCCCCN
Reactant: CCCCC1CO1
Product: CCCCC(O)CNCCCCCCCCCNCC(O)CCCC

Procedure:
Condensation of 1-hexene oxide and 1,9-nonanediamine affords N,N'-(1,9-nonylene)-bis[2-hydroxyhexylamine] (I: R = CH3 (CH2)3, R' = H, X = (CH2)9, Z = H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1.CS(C)=[O:22].C(=O)([O-])O.[Na+]>O>[CH:2]([C:3]1[CH:19]=[CH:18][C:6]2[S:7][CH:8]=[C:9]([C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=1)=[O:22]
Reactant: CS(C)=O
Reactant: COC=C(C(=O)OC)c1csc2ccc(CBr)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC=C(C(=O)OC)c1csc2ccc(C=O)cc12
Temperature: 85 °C

Procedure:
A mixture of 2 g of methyl α-(5-bromomethyl-3-benzo[b]thienyl)-13-methoxyacrylate (see Example 11), 16 ml of dimethyl sulfoxide and 0.5 g of sodium hydrogencarbonate is heated at 85° C. for 2.5 hours. Water is subsequently added, and the mixture is extracted using ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is then purified by chromatography on silica gel using diethyl ether/n-hexane (2:1). Recrystallization from methylene chloride/n-hexane gives methyl α-(5-formyl-3-benzo[b]thienyl)-β-methoxyacrylate as colourless crystals, m.p. 134°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.[C:41](O)(C(F)(F)F)=O.C=O>O1CCOCC1>[CH3:1][O:2][C:3]([CH:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=5)=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:30][C:31]=2[CH2:41][N:32]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[O:40]
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OCC(c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Solvent: C1COCCO1
Product: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 60 °C

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-{2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-propionic acid methyl ester (2.1 g) was deprotected according to General Procedure C. The resulting material was dissolved in dioxane (20 mL) and TFA (4 mL) and solid paraformaldehyde (300 mg) added. The reaction mixture was heated for 2 h at 60° C. and concentrated. The resulting material was dissolved in DCM and aqueous sodium bicarbonate and ditert-butyl pyrocarbonate (1.5 g) added. The layers of the reaction mixture were separated and the aqueous layer was extracted twice with 50. mL of DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to provide a yellow solid. The residue was purified by silica gel chromatography (10/90 to 30/70 ethyl acetate/hexanes in 10% increments) to obtain the desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.45 (d, 1H), 7.32 (d, 2H), 7.24 (m, 2H), 6.96 (d, 2H), 6.77 (s, 1H), 6.72 (d, 2H), 5.04 (m, 1H), 5.02 (s, 2H), 4.73 (m, 1H), 4.60 (m, 1H), 4.40 (m, 1H), 4.26 (m, 1H), 3.97 (m, 1H), 3.64 (d, 3H), 3.02-3.20 (m, 2H), 1.54 and 1.44 (s, 9H).