Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[N:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][C:9]2=[O:17])[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([Cl:18])[C:6]([N:8]3[N:12]=[C:11]([C:13]([CH3:15])([CH3:14])[CH3:16])[O:10][C:9]3=[O:17])=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nn(-c2cc3nc(N)sc3cc2Cl)c(=O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
3-(5-Amino-2-chlorophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (38.28 g) was dissolved in 95% acetic acid (138.20 g), and ammonium thiocyanate (27.64 g) was added thereto, followed by stirring at room temperature for 3 hours. To the resultant mixture, a solution of bromine (27.64 g) in acetic acid (41.46 g) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was combined with hot water (274.7 ml), heated to 100° C. and filtered while hot. The filtrate was neutralized with sodium carbonate and extracted with ethyl acetate. Teh extract was washed with water, dried and distilled under reduced pressure to give 3-(2-amino-6-chlorobenzothiazol-5-yl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (39.06 g) as a resinous substance.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH2:17][CH3:18])[N:13]=[CH:12][N:11]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27](=[O:34])[CH2:28][N:29]1[CH:33]=[N:32][CH:31]=[N:30]1>C1COCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH:17]([CH3:18])[C:27]([C:21]2[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=2[F:19])([OH:34])[CH2:28][N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[N:13]=[CH:12][N:11]=1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ncnc(Cl)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -70 °C
Reaction time: 3 h

Procedure:
To a solution of LDA (20 mmol) in THF1) (50 ml) (prepared by a similar method to that used in Example 1) under a nitrogen atmosphere and at -70° C. was added dropwise a solution of the product of part (ii) (3.2 g, 20 mmol) in THF1 (30 ml) over 15 minutes. The resulting mixture was stirred at this temperature for 3 hours. To the resulting solution was added a solution 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (4.46 g, 20 mmol) in THF (50 ml) and the mixture was maintained at -70° C. for 1 hour and then at -50° C. for a further 1 hour. The reaction was quenched by the addition of a solution of glacial acetic acid (1.2 g) in water (10 ml) and the mixture was allowed to warm to room temperature. The organic phase was separated, the aqueous phase extracted with ethyl acetate (20 ml) and the combined organic layers were dried over magnesium sulphate and concentrated under reduced pressure. Column chromatography of the residue on silica using 3:2 ethyl acetate/diethyl ether as the eluant first gave, after combination and evaporation of appropriate fractions and trituration with diethyl ether, the title compound, enantiomeric pair B (0.94 g, 12%), m.p. 92° C. Found: C,49.93; H,3.57; N,18.17; C16H13ClF3N5O requires: C,50.06; H,3.39; N,18.25%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[C:34]([O-:37])(=[O:36])[CH3:35].[Na+]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][O:37][C:34](=[O:36])[CH3:35])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [Na+]
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCOC(C)=O)CC2)nc1N

Procedure:
[4-Amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) was reacted with sodium acetate in an analogous manner as described in Example 227 to give acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester. The crude acetic acid 3-[4-[4-amino-5-(2,3-difluoro-6-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-sulfonyl]-propyl ester was hydrolyzed with 5% potassium hydroxide to give [4-amino-2-[1-(3-hydroxy-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone. HR-MS (ES, m/z) calculated for C20H26N5O5SF2 [(M+H)+] 486.1617, observed 486.1623.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10](=[O:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(Cl)Cl.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:37])/[CH:11]=[CH:12]/[C:13]2[N:17]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:16]=[N:15][CH:14]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(C(=O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc(C(O)/C=C/c2cncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Reaction time: 1 h

Procedure:
To a solution of the product from Step E (8.89 g, 18.4 mmol) in methanol (200 mL)/methylene chloride (50 mL) at 0° C. was added sodium borohydride (695 mg, 18.4 mmol). After stirring for 1 hour, the reaction was quenched by the addition of sat. aq. NH4Cl until H2 evolution ceased. The solvents were removed in vacuo and the residue was partitioned between methylene chloride (200 mL) and water (200 mL). The layers were separated and the aqueous layer was washed with methylene chloride (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the title compound as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[N:29]=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[N:29]=[CH:28][N:27]([CH2:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]4)[C:24]2=[N:25][CH:26]=1)=[O:20]
Reactant: COC(=O)c1cnc2[nH]cnc2c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CO)c21
Product: COC(=O)c1cnc2c(c1)ncn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Yield: 30 %

Procedure:
Compound 35 was prepared following general method 3A, using compound 17 as a starting material and 3H-Imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester as the heterocycle. Yield: 30%.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH3:30])[C:9](=[O:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C(#N)C>[CH2:1]([N:8]([CH2:29][CH3:30])[C:9](=[O:28])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:25][CH2:26][CH3:27])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.112 g, 0.27 mmol) in acetonitrile (14 mL) was added aqueous 0.10 M LiOH (7 mL) and the reaction mixture was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.096 g (92%) of a colourless oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][Si:37]([CH3:53])([CH3:52])[CH2:38][CH2:39][O:40][CH2:41][O:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][C:47](=[O:48])[C:46]3[CH:50]=[CH:51][C:43]([O:42][CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:52])([CH3:36])[CH3:53])=[CH:44][CH:45]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(OCOCC[Si](C)(C)C)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described under Example 24(l), from tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 4-(2-trimethylsilanyl-ethoxymethoxy)-benzoic acid using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[2-[4-(2-trimethylsilanyl-ethoxymethoxy)-benzoyloxy]-ethoxy]-phenyl]-piperidine-1-carboxylate as a colourless, amorphous solid; MS: 728 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc([Si](C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc([Si](C)(C)C)cc1
Yield: 90.7 %

Procedure:
The product of Step A (59 g, 0.33 mole) was dissolved in carbon tetrachloride (700 mL). To this solution was added N-bromosuccinimide (59 g, 0.33 mole) and benzoyl peroxide (ca. 200 rag) in one portion. The reaction mixture was heated to reflux for 2.5 hours while being irradiated with a 275 watt sunlamp. After cooling, the solid succinimide was removed by filtration and the filtrate was washed with saturated aqueous NaHSO3. Drying (MgSO4) and concentration gave an oil (77 g, 91% yield) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[Cl:11].C(O)(=O)C.[N:17]([O-])=O.[Na+].O.O.Cl[Sn]Cl>O.Cl>[ClH:11].[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([NH:10][NH2:17])[CH:7]=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(NN)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 183.3 %

Procedure:
To 5-amino-2-chloro-benzoic acid methyl ester (14.0 g, 75.0 mmol) in water (100 mL) was added concentrated HCl (100 mL), followed by glacial acetic acid (100 mL). The solution was stirred at ambient temperature for 15 minutes. The reaction was then cooled to 0° C., and a solution of sodium nitrite (5.69, 82.5 mmol) in water (15 mL) was added dropwise over 30 minutes, maintaining the temperature at 0° C. The resulting reaction was stirred for 30 minutes at 0° C., then a solution of SnCl2.2H2O (50.8 g, 225 mmol) in concentrated HCl (100 mL) was added over 30 minutes, maintaining the temperature at 0° C. The slurry was stirred at 0° C. for 30 minutes, and the resulting precipitate collected by filtration, washed with water, followed by hexane. The solid was dried in a vacuum oven at 50° C. to give the title compound (16.3 g).
Reaction SMILES: [C:1]1([C:7]2([C:11](Cl)=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH2:22])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:22][C:11]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10][CH2:9][CH2:8]2)=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(Cl)C1(c2ccccc2)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)C2(c3ccccc3)CCC2)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phenylcyclobutanecarbonyl chloride (129 g) in dichloromethane (500 ml) was added under nitrogen over 1.5 hours to a stirred mixture of 4-methoxyphenethylamine (99.5 g), dichloromethane (500 ml) and triethylamine (110 ml). The mixture was stirred at 20°-25° C. for one hour and allowed to stand for 16 hours. The reaction mixture was washed with 2N hydrochloric acid, water and 2N aqueous sodium hydroxide solution, dried and evaporated to give N-[2-(4-methoxyphenyl)ethy]-1-phenylcyclobutane carboxamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)(C)[CH3:12].ICC>C1COCC1>[CH2:11]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH3:12]
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2ccccc2s1

Procedure:
2-Ethylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3 ml), iodoethane (8.9 mmoles, 0.72 ml) and THF (20 ml). 1.2 g (99%) of a yellow liquid was isolated.
Reaction SMILES: C(S[S:4][C:5]#[N:6])#N.[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.[OH-].[NH4+]>O>[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[C:11]([S:4][C:5]#[N:6])=[CH:10][CH:9]=1
Reactant: Nc1cccc2c([N+](=O)[O-])cccc12
Reactant: N#CSSC#N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: N#CSc1ccc(N)c2cccc([N+](=O)[O-])c12
Reaction time: 1 h

Procedure:
The cold thiocyanogen solution was added to the stirred solution of 1-amino-5-nitronaphthalene, maintaining the temperature at 5°-15° C. The mixture was stirred a further one hour at 5°-15° C. and then made just alkaline (pH 7-8) by addition of concentrated ammonium hydroxide solution. The reaction mixture, after filtering from a small amount of insoluble material, was evaporated to dryness. The solid obtained was stirred with water, filtered, washed and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=2)=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(F)c4)nc23)ccn1
Yield: 38.6 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (151 mg, 0.5 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (85 mg, 39%). MS (ISP) 441.5 [(M+H)+]; mp 250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH2:21])=[CH:15][CH:14]=1.[O:22]=[C:23]1[CH2:28][S:27][C:26]2[CH:29]=[CH:30][C:31]([CH:33]=O)=[N:32][C:25]=2[NH:24]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CCO>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH2:33][C:31]2[CH:30]=[CH:29][C:26]3[S:27][CH2:28][C:23](=[O:22])[NH:24][C:25]=3[N:32]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(-c3ccc(CCN)cn3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(-c3ccc(CCNCc4ccc5c(n4)NC(=O)CS5)cn3)c2n1
Reaction time: 24 h
Yield: 30.2 %

Procedure:
To a stirred solution of 2-[6-(6-methoxy[1,5]naphthyridin-4-yl)pyridin-3-yl]ethylamine (0.94 mmole) in dry CH2Cl2 (25 mL) and dry EtOH (10 mL) at RT was added 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxaldehyde (0.18 g, 0.94 mmole) and Na2SO4 (500 mg). After 24 h, the reaction contents were concentrated and dried under high vacuum. To a stirred solution of the crude imine in dry EtOH (25 mL) at RT was added NaBH4 (36 mg, 0.94 mmole). After 24 h, the reaction solution was concentrated under vacuum and to the residue was added 1M HCl (5 mL) and EtOAc (50 mL). After stirring for 1 h, 6M NaOH (1 mL) was added and the organic layer was separated, dried (Na2SO4) and concentrated. Purification on reverse-phase HPLC (CH3CN/H2O, 10-90%) afforded the title compound (0.13 g, 30%) as light yellow solid: 1H NMR (400 MHz, CDCl3) δ 9.89 (br s, 1H), 9.15 (m, 1H), 8.90 (m, 1H), 8.57 (d, J=9.1 Hz, 1H), 8.45 (d, J=9.1 Hz, 1H), 8.20 (m, 2H), 7.51 (m, 1H), 7.22 (d, J=9.1 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 4.24 (m, 2H), 4.02 (s, 3H), 3.55 (m, 2H), 3.41 (m, 2H), 3.30 (s, 2H). LC-MS (ES) m/e 459 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH3:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)nnc1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccccc2)nnc1Cl
Temperature: 80 °C

Procedure:
3,6-Dichloro-4-methylpyridazine (1.00 g, 6.1 mmol) was mostly dissolved in dioxane (22.5 mL) then added phenylboronic acid (0.82 g, 6.7 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.25 g, 0.31 mmol) and a solution of cesium carbonate (6.0 g, 18 mmol) in water (7.5 mL). The reaction mixture was heated at 80° C. for 6 hours. The reaction mixture was concentrated under vacuum and the remaining solid was triturated with water. The solid was collected on a glass frit, washing well with water. The sample was purified by flash chromatography eluting with 1:4 ethyl acetate/hexane to afford 3-chloro-4-methyl-6-phenylpyridazine as an off-white solid.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11](=[O:30])[O:12][C:13]=2[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24](Cl)[CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1.[CH2:31](O)C>>[ClH:28].[C:3]1([CH3:31])[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11](=[O:30])[O:12][C:13]=2[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:5][CH:4]=1
Reactant: O=c1oc(CCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(-c2ccc(F)cc2)o1
Reactant: CCO
Agent: Cl
Product: Cc1ccc(-c2oc(=O)oc2CCN2CCN(c3ccccc3)CC2)cc1

Procedure:
4-(4-fluorophenyl)-5-[2-(4-(3,5-dichlorophenyl)-1-piperazinyl)ethyl]-1,3-dioxol-2-one hydrochloride m.p.=277°-9° C. (from ethanol
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([C:34]2[CH2:35][CH2:36][NH:37][CH2:38][CH:39]=2)=[C:31]([CH3:33])[CH:32]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][N:15]=2)[N:12]=[CH:11][C:10]=1[C:24]([NH:26][C:27]1[CH:28]=[N:29][C:30]([C:34]2[CH2:35][CH2:36][N:37]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])[CH2:38][CH:39]=2)=[C:31]([CH3:33])[CH:32]=1)=[O:25]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Reactant: CC(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(S(=O)(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Isopropylsulfonyl chloride (72 μl) was added to a suspension of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (221 mg) described in Reference Example 170 and potassium carbonate (138 mg) in N,N-dimethylformamide (1.7 ml), and stirred at room temperature for 5 hours. Water was added and the precipitated solid was purified with silica gel chromatography (chloroform/methanol) to give the titled compound (62 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[CH:35]1([CH2:40]O)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH:35]1([CH2:40][O:25][C:22]2[CH:23]=[CH:24][C:19]([C@H:17]3[CH2:16][O:15][C:11]4=[CH:12][C:13]5[CH2:14][C@@H:5]([C:3]([OH:2])=[O:4])[N:6]([C@H:26]([C:29]6[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=6)[CH2:27][CH3:28])[CH2:7][C:8]=5[CH:9]=[C:10]4[O:18]3)=[CH:20][CH:21]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Reactant: OCC1CCCC1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with cyclopentylmethanol according to General Procedure K and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg). The title compound (17 mg) was prepared from (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 781.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[O:31][C:14]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([Cl:7])[CH:15]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 150 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Potassium carbonate (5.53 g) was added to a DMF solution (70 ml) of 2-chloro-4-fluorobenzaldehyde (3.35 g) and 3-benzyloxyphenol (4.23 g) and the solution was stirred for 3 hours while heated to 150° C. The reaction mixture was decanted into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1). In this manner, the desired product (6.73 g) was obtained as a colorless powder.