Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:54][N:55]1[CH:59]=[CH:58][C:57]([CH:60]=O)=[N:56]1>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[CH2:60][C:57]1[CH:58]=[CH:59][N:55]([CH3:54])[N:56]=1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Cn1ccc(C=O)n1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1Cc1ccn(C)n1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (35 mg) was treated with 1-methyl-1H-pyrazole-3-carbaldehyde according to General Procedure D to give (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(1-methyl-1H-pyrazol-3-ylmethyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-propionic acid methyl ester (25 mg). This was hydrolyzed according to General Procedure B to give the title compound (21 mg). LCMS (m/z): 830.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.NC1C=C(C=CC=1Cl)C#N.[O:23]=[C:24]1[NH:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:25][C:24]3=[O:23])=[N:6][C:5]=2[CH:7]=1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: N#Cc1ccc2sc(Cl)nc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#Cc1ccc(Cl)c(N)c1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cc(C#N)ccc3s2)C(=O)C1
Temperature: 100 °C
Yield: 35 %

Procedure:
To a flask charged with 2-chloro-1,3-benzothiazole-5-carbonitrile [prepared from 3-amino-4-chlorobenzonitrile following the procedure described in US Publication 2009/0197862, Example 267] (146 mg, 0.75 mmol) and a stir bar was added tert-butyl 3-oxopiperazine-1-carboxylate (225 mg, 1.1 mmol), Pd2(dba)3 (69 mg, 0.075 mmol), Xantphos (87 mg, 0.15 mmol), cesium carbonate (370 mg, 1.1 mmol), and dioxane (10 mL). The mixture was purged three times with nitrogen, and heated to 100° C. under N2 for 16 hours. The reaction was diluted with EtOAc, adsorbed onto silica gel, and purified by silica gel chromatography (Hexanes:EtOAc 1:1) to provide tert-butyl 4-(5-cyano-1,3-benzothiazol-2-yl)-3-oxopiperazine-1-carboxylate (95 mg, 35% yield). The carboxylate was further treated with TFA to remove the Boc group. After removal of TFA, the residue was dissolved in aqueous sodium carbonate, extracted with DCM, dried over sodium sulfate, and concentrated to provide the free base of 2-(2-oxopiperazin-1-yl)-1,3-benzothiazole-5-carbonitrile. LC-MS (IE, m/z): 259 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[OH:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CO>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:41]2[CH2:42][CH2:43][CH:38]([C:37]([OH:36])([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:39][CH2:40]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C2(CCN3CCC(C(O)(c4ccccc4)c4ccccc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.50 g, 0.96 mmol), 4-(hydroxy-diphenyl-methyl)-piperidine (0.39 g, 1.44 mmol), and potassium carbonate (0.60 g, 4.34 mmol) in dimethylformamide (30 mL). Heat to 80° C. After 48 hours, cool and evaporate in vacuo to obtain a residue. Partition the residue between ethyl acetate and water. Extract the organic layer with water and a saturated solution of potassium carbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5/1 ethyl acetate/methanol to give a foam. Combine the foam with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo at 65° C. to obtain the title compound: Rf=0.21 (silica gel, 5/1 ethyl acetate/methanol); mp; 95-97° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=O)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7](=[S:19])[NH2:9])[CH2:3][CH2:2]1
Reactant: NC(=O)C1CCOCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=S)C1CCOCC1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of tetrahydro-2H-pyran-4-carboxamide (9.47 g, 73.3 mmol) and Lawesson's reagent (14.83 g, 36.7 mmol) in THF (98 mL) was heated to reflux for 6 h. The reaction was cooled to rt, poured into saturated aqueous NaHCO3 (200 mL) and extracted with diethyl ether (4×100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residual solid was triturated with 1:1 EtOAc:hexanes (100 mL) and filtered to collect the solid. The filtrate was concentrated and re-subjected to trituration and filtration using the same conditions. The combined solids were dried under vacuum to afford tetrahydro-2H-pyran-4-carbothioamide (4.91 g, 32.1 mmol, 43.8% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (br. s., 1H), 6.84 (br. s., 1H), 3.94-4.32 (m, 2H), 3.31-3.62 (m, 2H), 2.52-3.03 (m, 1H), 1.81-1.93 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([CH3:31])([CH3:30])[CH2:13][CH2:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]#[N:17])[CH2:8]1.[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[OH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:34]=[CH:33][CH:32]=[C:4]([CH2:5][O:6][C@H:7]2[CH2:11][CH2:10][N:9]([C:12]([CH3:30])([CH3:31])[CH2:13][CH2:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]#[N:17])[CH2:8]2)[CH:3]=1
Reactant: OB(O)c1ccccc1O
Reactant: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(Br)c2)C1
Product: CC(C)(CCC(C#N)(c1ccccc1)c1ccccc1)N1CC[C@H](OCc2cccc(-c3ccccc3O)c2)C1

Procedure:
The title compound was prepared from the product of example 55 and 2-hydroxyphenylboronic acid, using the same method as that described for example 56. The crude compound was purified by column chromatography on silica gel, eluting with ethyl acetate followed by dichloromethane:methanol, 95:5, to afford the desired product as pale brown foam in 61% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:17])[C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28](I)=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]#[C:1][C:3]3[CH:4]=[C:5]([CH3:17])[C:6]([NH:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:7][CH:8]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Clc1ccc(-c2ccc(I)nc2)cc1
Reactant: C#Cc1cnc(NCCN2CCCC2)c(C)c1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cnc1NCCN1CCCC1

Procedure:
Prepared analogously to Example 15e from 69 mg (0.3 mmol) (5-ethynyl-3-methyl-pyridin-2-yl)-(2-pyrrolidin-1-yl-ethyl)-amine and 95 mg (0.3 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine, while after working up the crude product is purified by chromatography on Alox (cyc/EtOAc 6:4).
Reaction SMILES: [OH:1][C:2]1([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:16]=[C:15]([O:17][CH3:18])[C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)=[C:3]1[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>ClCCl>[CH3:18][O:17][C:15]1[C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=[C:8]([C:4]2[C:5](=[O:7])[O:6][C:2]([C:32]3[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)([O:1][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[C:3]=2[CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:16]=1
Reactant: OCCN1CCOCC1
Reactant: COc1ccc(C2(O)OC(=O)C(c3cc(OC)c4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Solvent: ClCCl
Product: COc1ccc(C2(OCCN3CCOCC3)OC(=O)C(c3cc(OC)c4c(c3)OCO4)=C2Cc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 24 h

Procedure:
To 125 mL dichloromethane was added 5-Hydroxy-3-(7-methoxy-benzo[1,3]dioxol-5-yl)-5-(4-methoxy-phenyl)-4-(3,4,5-trimethoxy-benzyl)-5H-furan-2-one 3.25 g (6.06 mmol), giving a suspension. 4-(2-Hydroxyethyl)morpholine 3.24 g (24.76 mmol) was added, and the mixture was purged with anhydrous HCl gas until saturated. After 24 hours at room temperature, the mixture was evaporated in vacuo and the residue was suspended in warm ethyl ether and water. Decant the aqueous phase and wash the ether phase with 1 N NaOH, followed by water and saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to a glassy solid, 2.13 g. The product was identified by 1H NMR, MS [M--H]+ =650 Da.
Reaction SMILES: Cl.[C:2]1(=[C:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(O)C.CO.[C].[Pd]>[CH:2]1([CH:8]2[C:12]3[C:13]([CH3:33])=[C:14]([N:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:35])[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=C3CCCCC3)C(C)(C)O4)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C3CCCCC3)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
A mixture of 1-(3-cyclohexylidene-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine hydrochloride obtained in Example 45 (390 mg, 0.79 mmol), 10% palladium-carbon (300 mg) in ethanol (10 ml) and methanol (10 ml) was stirred at room temperature under hydrogen pressure of 4–5 atmospheres for 8 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was diluted with 10% aqueous potassium carbonate, and the aqueous layer was made alkaline and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain 95 mg (yield 26%) of the title compound via recrystallization (ethanol). mp. 119–121° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1O.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CCOCC.C(O)C>[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Oc1ccccc1F
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCO
Product: CN1CC[C@@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under a nitrogen atmosphere at 5°-10° C. over a 90 minute period to a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 2-fluorophenol and 125 ml of dry benzene. After the addition, the mixture is stirred for 18 hours at room temperature, then filtered, and the solid waste is washed well with hexane. The filtrate is concentrated in vacuo to an oil which is stirred 18 hours with hexane. A gummy solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is taken up in ether and extracted with 2 N HCl solution. The acid extracts are extracted with dichloromethane. The dichloromethane extracts are washed with 10% by weight of aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford and oil. The oil is chromatographed on silica gel, using acetone as solvent. A purified free base is obtained as an oil. This material is dissolved in 75 ml of ether and treated dropwise with a solution of 1.44 g of fumaric acid in a mixture of 25 ml of absolute ethanol and 50 ml of ether. Scratching of the resulting solution causes crystallization to occur. The solid is filtered, washed with ether, and dried to afford a colorless solid of trans-4-(2-fluorophenoxy)-1-methyl-3-phenylpiperidine furmarate hemihydrate, m.p. partially melts 149°, 161°-167° C. Recrystallization from ethyl acetate affords the product having mp s 154, 156° C., dec.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([S:16]([O-:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CS(C)=O>[C:10]1([S:16]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 180 °C
Yield: 76.5 %

Procedure:
A microwave vessel was charged with 1 g of 4-chlorobenzaldehyde in 6 mL of DMSO and 1.75 g of sodium benzenesulfinate. The vessel was sealed and heated in a microwave reactor at 180° C. for 1.5 hours. The mixture was cooled and poured into 12 mL of ice water. Filtered and the solid was purified by flash chromatography using ethyl acetate/hexane as eluent mixtures to afford 1.34 g of the title compound. 76% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6])=[N+]=[N-]>CO.Cl.[Pd]>[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6]
Reactant: COc1ccccc1C(=O)CN=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccccc1C(=O)CN
Yield: 122.4 %

Procedure:
Dissolve 2-azido-1-(2-methoxy-phenyl)-ethanone (3.54 g, 18.5 mmol) in 1328 ml of MeOH and 9 ml of concentrated HCl. Add 943 mg of 10% Pd/C and expose the reaction mixture to 60 psi of H2 for 5 hours at ambient temperature. Filter the catalyst off through a pad of celite and concentrate the filtrate in vacuo to afford 3.74 g of crude 2-amino-1-(2-methoxyphenyl)-ethanone as the hydrochloride salt.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[C:7]2=[O:18])[CH2:29][CH2:30]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Yield: 91 %

Procedure:
To a solution of 101 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 0.152 ml (3 equivalents) of 1-(2-pyridyl)piperazine, followed by heating under reflux for 8 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 116 mg of the desired compound (yield 91%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.ClCCCl.CC(O)(C)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]2)=[CH:25][CH:24]=1.CCN(CC)CC>CO.O.[Cl-].[Zn+2].[Cl-]>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30]3)=[CH:27][CH:28]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Zinc chloride (1.0 M in Et2O) (1.40 mL, 1.40 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (180 μL, 1.29 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under a stream of nitrogen gas. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (I136) (0.307 g, 1.17 mmol) in 1:1 DCE/tBuOH (10 mL) was added. A solution of NEt3 (0.180 mL, 1.29 mmol, 1.1 eq) in 1:1 DCE/t-BuOH (5 mL) was next added dropwise at 0° C. The reaction mixture was vigorously stirred for a further 30 minutes at 0° C. after the final addition and then at room temperature for 16 hours. The solvent was removed in vacuo to afford a brown oily residue which was purified by column chromatography on silica gel (0-50% EtOAc in petroleum benzine 40-60° C.) to yield a pale yellow solid. The solid was suspended in MeOH (15 mL) and water (15 mL). The precipitate was filtered to afford the title compound (I137) (0.449 g, 87%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3)1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.40 (s, 1H), 7.26 (s, 2H), 3.92-3.73 (m, 1H), 3.69-3.51 (m, 1H), 3.48-3.22 (m, 3H), 2.26 (s, 1H), 2.03-1.90 (m, 1H), 1.48 (s, 9H). LCMS Method C: rt 6.68 min; m/z 443.0 [M+H]+, 441.1 [M−H]−.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([N+:23]([O-])=O)=[C:21]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:20]=[C:19]([CH3:33])[C:18]=1[CH3:34].C(O)C.O1CCCC1>O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:18]([CH3:34])=[C:19]([CH3:33])[N:20]=[C:21]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:22]=1[NH2:23]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCCl)c1C
Yield: 126.3 %

Procedure:
A solution of sodium dithionite (24.01 g, 137.9 mmol) in water (90 mL) was added to a mixture of N-(6-chlorohexyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine (10.42 g, 27.58 mmol) and ethanol (276 mL). After about 4 hours sodium dithionite (6.71 g) in water (20 mL) was added to the reaction mixture. About 1 hour later tetrahydrofuran (100 mL) was added. When analysis by thin layer chromatography indicated that the reaction was complete, the reaction mixture was filtered to remove solids. The solids were rinsed with ethanol. The rinses and the filtrate were concentrated under reduced pressure. The residue was diluted with toluene (200 mL) and then concentrated under reduced pressure to remove the bulk of the solvent. The residue was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was separated, combined with saturated aqueous sodium bicarbonate to adjust to pH 8 and then extracted with ethyl acetate. The combined organics were washed with brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was combined with toluene and then concentrated under reduced pressure to provide 12.12 g of N4-(6-chlorohexyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)C)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO>[Si:33]([O:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:14]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])([C:46]([CH3:49])([CH3:47])[CH3:48])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC(c1ccccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OCc1ccccc1C(CCCCCO)S(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
In methanol (30 ml) was dissolved t-butyl [[6-[2-[(t-butyldiphenylsilyloxy)methyl]phenyl]-6-[(4-chlorophenyl)sulfonyl]hexyl]oxy]dimethylsilane (830 mg, 1.13 mmol), followed by the addition of p-toluenesulfonic acid monohydrate (25 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 2 hours. Triethylamine (0.080 ml, 0.57 mmol) was added and then, the residue obtained by concentrating the resulting mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the dichloromethane:methanol=100:1 eluate was concentrated under reduced pressure, whereby the title compound (580 mg, 0.934 mmol, 83%) was obtained as a colorless oil.