Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH:5](C(OC)=O)[CH2:4]1)#[N:2].CS(C)=O.[Cl-].[Na+]>O>[C:1]([C:3]1([C:14]2[C:23]3[O:22][CH2:21][CH2:20][O:19][C:18]=3[C:17]([O:24][CH3:25])=[CH:16][CH:15]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC)c3c2OCCO3)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C2(C#N)CCC(=O)CC2)c2c1OCCO2
Temperature: 150 °C
Reaction time: 5 h
Yield: 83.5 %

Procedure:
A mixture of Compound 1c (5.0 g, 15 mmol) obtained in Step C, DMSO(50 mL), water (5 mL), and sodium chloride (5.0 g) was stirred at 150° C. for 5 hours. The mixture was allowed to cool, and added water, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (eluted with hexane/ethyl acetate=3/1) to give Compound 1 (3.6 g, 86%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:34]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][C:35]=1[C:36]#[N:37]
Reactant: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A mixture of 4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (206 mg, 0.45 mmol), 2-bromo-5-(trifluoromethyl)-benzonitrile (75 mg, 0.3 mmol), Pd(PPh3)4 (34.7 mg, 0.03 mmol), Na2CO3 (190.8 mg, 1.8 mmol) in dioxane/water (9/1, 1.5 mL), was heated at 95° C. for approximately 16 hrs after degassing of the solvent with a stream of nitrogen. The reaction was allowed to cool to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was further washed with brine and dried with MgSO4. The filtrate was evaporated and the residue purified by preparative TLC [eluent: 40% acetone in hexane] to afford 4-chloro-3-(2-cyano-4-trifluoromethyl-phenyl)-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide 10-1 (120 mg). MS [M+H]+: 502.9; tR=8.15 min. (method 2)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:22]1([C:26]2[O:30][N:29]=[C:28]([C:31]3[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=3[Cl:38])[C:27]=2[CH2:39]O)[CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:22]1([C:26]2[O:30][N:29]=[C:28]([C:31]3[C:32]([Cl:38])=[CH:33][N:34]=[CH:35][C:36]=3[Cl:37])[C:27]=2[CH2:39][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[C:16]4[C:11]([CH:12]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[CH:15]4)=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Reactant: OCc1c(-c2c(Cl)cncc2Cl)noc1C1CCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C4CCC4)cc3)cc2cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (50 mg, 0.18 mmol), [5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methanol (54 mg, 0.18 mmol) and triphenylphosphine (52 mg, 0.20 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.035 mL, 0.20 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes and allowed to stand at ambient temperature overnight. The next day the solution was adsorbed onto silica gel and purified by chromatography (first in 0-1.75% methanol in chloroform gradient elution then in 0-2% methanol in chloroform) to afford methyl 7-[4-({[5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate as a white solid (39 mg, 39%). 1H-NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.59 (s, 3H), 8.12 (s, 1H), 8.00-7.94 (m, 2H), 7.58 (d, J=9 Hz, 2H), 6.84 (d, J=9 Hz, 2H), 4.79 (s, 2H), 4.04 (s, 3H), 3.87-3.79 (m, 1H), 2.64-2.54 (m, 2H), 2.50-2.35 (m, 2H), 2.19-2.00 (m, 2H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].ClCCl.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][OH:26])[CH:19]=1>CN(C)C1C=CN=CC=1.CCCCCC.O>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([CH2:25][O:26][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11])[CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cnc(CO)cc1Br
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cnc(CO[Si](C)(C)C(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, imidazole (2.95 g, 43.3 mmol), 4-dimethylaminopyridine (481 mg, 3.94 mmol) and t-butylchlorodimethylsilane (6.53 g, 43.3 mmol) were added to a dichloromethane solution (100 ml) of (4-bromo-5-methylpyridin-2-yl)methanol (7.96 g, 39.4 mmol) under ice cooling. The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give the title compound (12.4 g, 39.4 mmol, quant.) as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[BrH:51].[Br-].[NH2:53][CH2:54][CH2:55][N+:56]12[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]1)[C@@H:58]([O:64][C:65](=[O:80])[C:66]([OH:79])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH2:57]2>CN(C=O)C>[Br-:51].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:53][CH2:54][CH2:55][N+:56]23[CH2:63][CH2:62][CH:59]([CH2:60][CH2:61]2)[C@@H:58]([O:64][C:65](=[O:80])[C:66]([OH:79])([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[CH2:57]3)=[O:15])=[CH:16][CH:17]=1
Reactant: Br
Reactant: NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-benzyloxybenzoic acid (0.126 mg, 0.55 mmol) in DMF (3 ml) is added diisopropylethylamine (0.3 ml) followed by HATU (0.155 mg, 0.55 mmol). The reaction mixture is stirred for 30 minutes at room temperature after which time a solution comprising (R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [Example 49(ii)] (0.200 g, 0.37 mmol) and the resulting mixture is stirred at room temperature over night. Purification is carried out using preparative C18 column chromatography eluting with acetonitrile: water to afford the titled compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[N:11]2[CH2:30][CH2:31][N:32]([CH3:35])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1CC1N2CCN(C)C(=O)C2=C(O)C(=O)N=1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:12]1[N:11]2[CH2:30][CH2:31][N:32]([CH3:35])[C:33](=[O:34])[C:10]2=[C:9]([OH:8])[C:14](=[O:15])[N:13]=1
Reactant: CN1CCn2c(Cc3ccccc3-c3ccccc3Cl)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CN1CCn2c(Cc3ccccc3-c3ccccc3)nc(=O)c(O)c2C1=O
Product: CN1CCn2c(Cc3ccccc3-c3ccccc3Cl)nc(=O)c(O)c2C1=O
Yield: 61.2 %

Procedure:
6-(2′-Chloro-biphenyl-2-ylmethyl)-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-02) (215 mg, 58.54%) was synthesized as an off-white solid from 9-benzyloxy-6-(2′-chloro-biphenyl-2-ylmethyl)-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (11-02) (400 mg, 0.887 mmol) following the procedure as described for 6-biphenyl-2-ylmethyl-9-hydroxy-2-methyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (12-01).
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[Br:19][C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([O:27][CH3:28])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:5][CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:22]([O:27][CH3:28])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: COc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 22 h

Procedure:
To a solution of (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00 mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) in N,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00 mmol). The mixture was heated to 100° C. After 22 h, the mixture was allowed to cool to 23° C. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane) afforded the title compound as an amber oil. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ 7.07-6.79 (m, 3H), 4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H), 2.16-1.80 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[C:11](OC([O-])=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>O1CCCC1>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCc1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
15.0 g of 2-Bromobenzylamine hydrochloride was dissolved in 100 ml of tetrahydrofuran, and a solution of 13 g of t-butyl dicarbonate in tetrahydrofuran (25 ml) was added thereto. The mixture was stirred at room temperature for 1 hour, and then the solvent was evaporated. The residue was dissolved in ethyl acetate, and washed successively with 1N hydrochloric acid and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated, to give 16.0 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:19][C:20]1[CH:25]=[C:24]([C:26](OCC)=[O:27])[CH:23]=[CH:22][N:21]=1)C(=O)C(F)(F)F)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([N:8]([CH3:31])[CH2:9][CH2:10][CH2:11][NH:12][CH2:19][C:20]1[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[CH:22][N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccnc(CN(CCCN(C)Cc2ccccc2)C(=O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: CN(CCCNCc1cc(CO)ccn1)Cc1ccccc1

Procedure:
By General Procedure U from ethyl 2-[(N-{3-[benzyl(methyl)amino]propyl}-2,2,2-trifluoroacetamido)methyl]pyridine-4-carboxylate using 5.0 equiv. of NaBH4. Purification by column chromatography gave the title product. 1H NMR (300 MHz, CDCl3) 8 ppm: 8.5 (dd, 1H), 7.80 (s, 1H), 7.6-7.3 (m, 1H), 4.6 (s, 2H), 4.3 (s, 2H), 3.6-3.2 (m, 4H), 2.8 (s, 3H), 2.2-2.0 (m, 2H), 1.7-1.3 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[N:16]=[CH:15]2.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.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>[Br:8][C:6]1[CH:7]=[C:2]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)[C:3]([CH3:9])=[N:4][CH:5]=1.[Br:1][C:2]1[CH:7]=[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[N:16]=[CH:15]3)[CH:5]=[N:4][C:3]=1[CH3:9]
Reactant: Cc1ncc(Br)cc1Br
Reactant: Cn1ncc2cc(CBr)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ncc(-c2ccc3c(cnn3C)c2)cc1Br
Product: Cc1ncc(Br)cc1-c1ccc2c(cnn2C)c1
Temperature: 105 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3,5-dibromo-2-methylpyridine (1.0 g, 3.99 mmol) and 5-(bromomethyl)-1-methyl-1H-indazole (772 mg, 4.38 mmol) in 1,4-dioxane (12 mL) was added Pd(PPh3)4 (231 mg, 0.20 mmol) and potassium carbonate solution (2 M aqueous, 6 mL, 12 mmol). The reaction mixture was stirred at 105° C. in a sealed tube for 1.5 h. The mixture was diluted with water (15 mL) and EtOAc (20 mL). The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by CombiFlash (EtOAc w/5% MeOH and Hexanes) to give 5-(5-bromo-2-methylpyridin-3-yl)-1-methyl-1H-indazole and 5-(5-bromo-6-methylpyridin-3-yl)-1-methyl-1H-indazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([O:28]CC)=[O:27])[CH2:25][CH2:24][CH2:23]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].O.[OH-].[Li+]>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:22]2([C:26]([OH:28])=[O:27])[CH2:23][CH2:24][CH2:25]2)[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(SC)cc3)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C3(C(=O)O)CCC3)cc(Cl)c2OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
A mixture of ethyl 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylate (325 mg, 0.70 mmol) and lithium hydroxide monohydrate (186 mg, 4.44 mmol) in MeOH/THF/Water solvent mixture (10 ml/10 ml/10/ml) was stirred for 3 h at room temperature. After completion of the reaction, the volatiles were removed under reduced pressure. The residue was diluted with water, acidified with 5% HCl solution and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Flash Column Chromatography to give 1-(5-chloro-4′-(methylthio)-6-(2,2,2-trifluoroethoxy)biphenyl-3-yl)cyclobutane carboxylic acid (265 mg) as a white solid. 1HNMR (CDCl3): 7.46 (d, 2H), 7.38 (s, 1H), 7.32 (d, 2H), 7.19 (s, 1H), 3.93 (q, 2H); 2.83 (m, 2H), 2.53 (s, 3H), 2.32 (m, 2H), 2.13 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:20]=2)[CH:12]=1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:39]1[CH2:38][CH2:37][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:21]3[N:20]=[C:19]([CH2:18][CH2:17][C:13]4[CH:12]=[C:11]([CH:16]=[CH:15][N:14]=4)[C:8]([NH2:9])=[O:10])[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:22]=3)=[CH:31][CH:32]=2)[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(N)=O)ccn4)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Trifluoroacetic acid (100 μL, 0.131 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(4-carbamoylpyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I130) (50 mg, 88 μmol) in DCM (4 mL) and the resulting mixture was stirred for 1 hour at room temperature. The volatiles were evaporated under reduced pressure and the residue purified by chromatography (SiO2, 0-50% MeOH/DCM) to give the title compound (I131) (28 mg, 68%) as a colourless solid; 1H NMR (400 MHz, d4-MeOD) δ 8.55 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 7.74 (s, 1H), 7.61 (dd, J=5.2, 1.3 Hz, 1H), 7.53 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 3.46 (d, J=12.7 Hz, 2H), 3.37 (t, J=7.0 Hz, 2H), 3.27 (dt, J=3.2, 1.6 Hz, 5H), 3.18-3.04 (m, 2H), 2.83 (ddd, J=12.1, 8.7, 3.6 Hz, 1H), 2.03 (d, J=13.8 Hz, 2H), 1.88 (ddd, J=16.7, 13.6, 3.8 Hz, 2H). LCMS Method C: rt 4.44 min; m/z 471.1 [M+1]+, 469.1 [M−1]−.
Reaction SMILES: [ClH:1].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.C([O:16][CH2:17][CH3:18])C.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)=[NH:23])[CH3:20]>C(O)C>[ClH:1].[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)=[NH:23])[CH3:20].[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:21][C:22]4[CH:18]=[C:17]([OH:16])[CH:31]=[CH:32][C:24]=4[N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: CCOCC
Agent: CCOC(=N)c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: CCO
Product: Oc1ccc2nc(-c3ccc4[nH]ncc4c3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1H-Indazole-5-carbonitrile hydrochloride (1.5 g) was suspended in ethanol (15 mL) at 0° C. The mixture was saturated with hydrogen chloride while the temperature was raised to room temperature. The reaction was then left overnight. Diethylether was added and the resulting precipitate, 1H-indazole-5-carboximidic acid ethyl ester.2HCl (1.39 g), was collected and dried in under high vacuum. According to synthetic method B except that pyridine (540 ?L) was added, from 4-amino-benzene-1,3-diol hydrochloride (0.36 mg) and 1H-indazole-5-carboximidic acid ethyl ester hydrochloride (0.71 g) was obtained the title compound (0.34 mg) as an off-white solid. The work-up of the reaction was modified as follows: After completion of the reaction, the mixture was diluted with ether and water, and filtered. The solids were washed with water and ether, and dried under high vacuum. MS: 252.4 (MH+); HPLC tR: 1.80 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.C(#N)C.C1C(=O)N([Br:20])C(=O)C1>>[Br:20][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1
Solvent: CC#N
Product: COc1ccc(Br)c(C)c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of 122 g (1.0 mol) of 1-methoxy-3-methylbenzene in 1 L of acetonitrile 178 g (1.0 mol) of NBS was added in small portions by vigorous stirring for 1 h at 10° C. The reaction mixture was stirred at ambient temperature overnight and then evaporated to dryness. The residue was dissolved in 1 L of n-hexane and filtered through glass frit (G2). The precipitate was additionally washed by 2×150 ml of n-hexane. The combined filtrate was evaporated to dryness to give 173 g (86%) of 1-bromo-4-methoxy-2-methylbenzene.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:21])[C:4]([C@@H:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5].C(OC(C)C)(=O)C.COC1C=CC(CN2C(C(O)=O)CSC2=O)=CC=1.CN1CCOCC1.C(Cl)(=O)C(C)(C)C.CONC>CCCCCCC>[CH3:1][O:2][N:3]([CH3:21])[C:4]([CH:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[O:5]
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(=O)N(C)OC)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CNOC
Agent: COc1ccc(CN2C(=O)SCC2C(=O)O)cc1
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCC
Solvent: CN1CCOCC1
Product: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
Preparation of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (A compound of Formula V): A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with an iso-propyl acetate solution of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid (310.0 g, 1.16 mol, approximately 3 L). The vessel was purged with nitrogen and cooled to 0° C. 4-Methyl-morpholine (130.0 g, 1.29 mol) was added while maintaining an internal reaction temperature below 5° C. Pivaloyl chloride (150.0 g, 1.24 mol) was added dropwise such that the internal reaction temperature was maintained below 5° C. The reaction was stirred at 0° C. for 45 minutes. N-Methoxy-methanamine (78.0 g, 1.28 mol) was added while maintaining an internal reaction temperature below 5° C. The reaction was monitored by HPLC and was considered complete when the ratio of the product to starting material was 4:1 (approximately 30 minutes after amine addition). The mixture was then washed with a 2.4 L portion of 0.1 M HCl, followed by 2.4 L of saturated NaHCO3. The organic phase was separated and concentrated to a final volume of 1.0 L by distillation. After a precipitate began to form, a 250 mL portion of n-heptane was added. The mixture was stirred vigorously. The solid was filtered and dried in a vacuum oven at 40° C. Approximately 250 g of 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide was obtained (70% yield). 1H NMR (300 MHz, DMSO) δ 7.15 (d, 8.9 Hz, 2H), 6.86 (d, 8.9 Hz, 2H), 4.49 (AB, JAB=14.4 Hz, ΔνAB=387.9 Hz, 2H), 4.40 (dd, J=8.8, 5.2 Hz, 1H), 3.79 (s, 3H), 3.46 (dd, J=11.0, 8.5 Hz, 1H), 3.38 (s, 3H), 3.21 (s, 3H), 3.15 (dd, J=11.0, 5.5 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 28.4, 32.9, 47.2, 55.8, 57.9, 61.9, 114.7, 128.5, 130.3, 159.5, 169.4, 172.3; [α]26.5D-93.5° (c=1.0 EtOH). The enantiomeric purity of (R)-(−)-3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide can be measure using the described HPLC method.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:15]([CH:28]=[CH2:29])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[CH2:28]([C:15]1[C:16]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:17]([C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:13][CH:14]=1)[C:18]([O:20][CH3:21])=[O:19])[CH3:29]
Reactant: [H][H]
Reactant: C=Cc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OC)c1OCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(NS(=O)(=O)c2ccc(F)cc2)c(C(=O)OC)c1OCC(=O)OC

Procedure:
A mixture of Example 467C (0.31 g, 0.7 mmole) in methanol (10 mL) was treated with 10% Pd/C (100 mg) at ambient temperature under one atmosphere of hydrogen for 16 hours. Filtration and evaporation of the solvent provided the desired product. 0.29 g, 97.5%. 1H NMR (DMSO-d6) δ 1.10 (t, 3H), 2.54 (q, 2H), 3.64 (s, 3H), 3.70 (s, 3H), 4.48 (s, 2H), 6.85 (d, 1H), 7.28 (d, 1H), 7.40 (t, 2H), 7.70 (t, 2H), 9.86 (s, 1H); MS (ESI(−)) m/e 424 (M−H)−.