Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[ClH:36].O1CCOCC1>CCOCC>[ClH:36].[C:1]([NH:4][C@:5]1([C:29]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 3 h

Procedure:
A 250 mL 3-neck round bottom flask was charged with (3R,4S)-tert-butyl 3-acetamido-3-(tert-butylcarbamoyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1-carboxylate (4.95 g, 10 mmol) and 4 N HCl/dioxane (50 mL). After stirring for 3 h the solution was diluted with ether (125 mL), stirred a few minutes, filtered, and the solid rinsed with ether, collected, and dried in vacuo to afford an HCl salt of the title compound. This was dissolved in water (30 mL) and treated with sodium hydroxide (0.5 g, 12.5 mmol). The aqueous solution was treated with sufficient potassium carbonate to render the free base product insoluble. The mixture was extracted with methylene chloride (75 mL, then 3×50 mL) and the combined organic solution was washed with saturated aqueous sodium chloride (30 mL), dried (Na2SO4), and concentrated to afford (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (3.40 g, 86%) as a white solid. NMR (CDCl3) δ 8.26 (br s, 1 H), 7.25 (s, 1 H), 3.86 (d, J=9.5 Hz, 1 H), 3.53 (t, J=9.5 Hz, 1 H), 3.20 (d, J=10 Hz, 1 H), 2.98 (m, 1 H), 2.74 (dd, J1=10 Hz, J2=7.5 Hz, 1 H), 2.02 (s, 3 H), 1.50 (m, 1 H), 1.33 (s, 9 H), 1.20-1.40 (m, 3 H), 1.22 (s, 12 H), 0.70-0.80 (m, 2 H). MS (m+1): 396.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[C:11]([N:15]([CH:42]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:16][CH2:17][N:18]([CH2:29][CH2:30][C:31]1[C:39]2[S:38][C:37](=[O:40])[NH:36][C:35]=2[C:34]([OH:41])=[CH:33][CH:32]=1)[C:19](=[O:28])[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:14])[CH:12]=[CH2:13]>C(O)C>[CH:42]1([N:15]([C:11](=[O:14])[CH2:12][CH2:13][NH:10][CH2:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:16][CH2:17][N:18]([CH2:29][CH2:30][C:31]2[C:39]3[S:38][C:37](=[O:40])[NH:36][C:35]=3[C:34]([OH:41])=[CH:33][CH:32]=2)[C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: NCCc1cccc(F)c1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1
Solvent: CCO
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1)C1CCCCCC1
Temperature: 50 °C
Reaction time: 32 h

Procedure:
2-(3-Fluorophenyl)ethanamine (0.573 mL) was added to benzyl {2-[acryloyl(cycloheptyl)amino]ethyl}[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate, prepared as in Example 23 step ii), (0.786 g) in ethanol (15 mL). The resulting solution was stirred at 50° C. for 32 h. The volatiles were removed in vacuo and the crude material was purified by flash silica chromatography, elution gradient 0.5:0.5:19 to 1:7:13 7M NH3 in methanol:ethanol:ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-title product (0.759 g) as a pale yellow foam.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:21]2[CH:22]=[CH:23][N:24]=[C:19]([Cl:18])[N:20]=2)=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc(Oc2ccc(OCc3ccccc3)cc2)n1
Reaction time: 2 h

Procedure:
To a stirred RT slurry of NaH (0.5 g of 60% oil dispersion, 12.6 mmol) in 15 mL DMF was added 4-benzyloxyphenol (2.40 g, 12.0 mmol). The mixture was stirred for 10 min before 2,4-dichloropyrimidine (1.79 g, 12.0 mmol) was added. A mild exotherm occurred. The reaction was stirred for 2 h and quenched with saturated aqueous NaHCO3. The reaction was diluted with EtOAc, the layers were separated, and the organic layer was washed twice with 2 N NaOH, once with brine, then dried over Na2SO4. The organic layer was filtered and concentrated in vacuo to yield crude title compound contaminated with minor impurities by H-NMR. MS (MH+)=NA; Calc'd 312.76 for C17H13ClN2O2.
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:18])[NH:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.BrBr.Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O1CCCC1.C(OCC)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[CH:16]=[CH:17][C:5]2[N:4]=[C:3]([NH:2][CH3:1])[S:18][C:6]=2[CH:7]=1
Reactant: CNC(=S)Nc1ccc(Cc2ccccn2)cc1
Agent: BrBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1nc2ccc(Cc3ccccn3)cc2s1
Yield: 12.1 %

Procedure:
To a solution of 2-[4-(3-methylthioureido)benzyl]pyridine (4.0 g) in chloroform (80 ml) was dropwise added the solution of bromine (0.9 ml) in chloroform (5 ml) at ambient temperature and the mixture was heated under reflux for 2.5 hours. The reaction mixture was added to 10% hydrochloric acid (60 ml) and the mixture was heated under reflux for 20 minutes. To the separated aqeuous layer was added a solution of ethyl acetate and tetrahydrofuran and the resultant solution was adjusted to pH 8 with potassium carbonate. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was purified by silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (4:1 V/V). The eluted fractions containing desired product were evaporated to give 6-[(2-pyridyl)methyl]-2-methylaminobenzothiazole (0.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:25]=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=3[Cl:24])[CH2:12][CH2:13][CH2:14][N:7]21.[CH2:27]([Mg]Br)[CH3:28]>O1CCCC1.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([Cl:24])=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=4[Cl:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:25]([OH:26])[CH2:27][CH3:28])=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)c(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(OC)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
To a solution of 9-chloro-1-(2,6-dichloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (146 mg, 0.356 mmol) in tetrahydrofuran (4 mL) was added dropwise ethylmagnesium bromide (3 M solution in diethyl ether, 0.237 mL, 0.711 mmol) at 0° C., and the mixture was stirred at 0° C. for 5 min. The reaction mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (137 mg, 0.311 mmol, 87%).
Reaction SMILES: [CH:1]1([C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[OH-].[K+]>CO>[CH3:10][O:9][C:7]([CH:4]1[CH2:5][CH2:6][CH:1]([C:11]([OH:13])=[O:12])[CH2:2][CH2:3]1)=[O:8]
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1CCC(C(=O)O)CC1
Yield: 33.3 %

Procedure:
To a stirred solution of dimethyl 1, 4-cyclohexane-dicarboxylate (20 g, Aldrich) in methanol (50 ml) was added a solution of potassium hydroxide (7.3 g) in methanol (75 ml). The reaction mixture was refluxed for 16 hours. After cooling the solvent was removed on a rotary evaporator. The residue was taken up in ether and water and extracted to remove unreacted starting diester. The aqueous layer was acidified with dilute hydrochloric acid and re-extracted with ether. The ether extracts were washed with brine and dried. Evaporation in vacuo gave a solid. Purification was achieved by recrystallization from ethyl acetate to yield 4-methoxycarbonylcyclohexanecarboxylic acid (6.2 g), m.pt 90.9° C.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH2:14])[C:8]2=[CH:7][N:6]=1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].N1C=CC=CC=1>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:10]=[C:9]2[NH:11][N:12]=[C:13]([NH:14][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:8]2=[CH:7][N:6]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1n[nH]c2nc(Oc3ccc(F)cc3F)ncc12
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To 6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-ylamine (60 mg, 0.228 mmol) in 2 mL dioxane was added ethanesulfonyl chloride (22.0 uL, 0.228 mmol) and pyridine (18.5 uL, 0.228 mmol). The reaction mixture was heated to reflux with stirring for two hours, then cooled and chromatographed through silica (0%-40% EtOAc in hexanes) to give 31 mg of ethanesulfonic acid [6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-amide, MP=226.0-226.9° C., MS(M+H)=356.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11].[OH-].[K+].Cl>O.CS(C)=O>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Oc1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
A mixture of 2,3,5-trichloropyridine (2.5 g, 13.7 mm), hydroquinone (3.02 g, 27.4 mm), KOH (3.07 g, 54.8 mm) and DMSO (10 ml) is heated to 160° for 3 hours. The mixture is poured into water, acidified with dilute HCl and extracted with ether. The ethereal solution is washed, dried and evaporated to dryness. The crude product is chromatographed on silica gel to give crystalline 4-(3,5-dichloropyridyloxy)phenol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14](Br)[C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:27])[N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[CH:17][CH:16]=2)[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OB(O)c1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Yield: 74.1 %

Procedure:
Compound 1A (4.0 g, 8.8 mmol), 8-quinolineboronic acid (3.0 g, 17.6 mmol), POPd (0.088 g, 0.18 mmol), and K2CO3 (3.6 g, 26.4 mmol) in iPrOH (90 mL) were stirred in a preheated 100° C. oil bath under nitrogen for 20 h. The reaction was filtered through celite and concentrated. The material was purified by chromatography on silica gel (gradient 2-5% MeOH in CH2Cl2) to give a yellow solid 1B (3.27 g, 74%). 1H NMR (500.333 MHz, CDCl3) δ 8.91 (dd, J=4.0, 1.6 Hz, 1H), 8.13 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (dt, J=9.5, 3.5 Hz, 1H), 7.50 (d, J=2.5 Hz, 2H), 7.37-7.33 (m, 5H), 3.86 (br s, 2H), 3.68 (br s, 2H), 3.59 (br s, 2H), 3.52-3.43 (m, 3H), 3.34-3.23 (m, 2H), 3.03 (s, 3H), 2.57-2.52 (m, 2H), 2.01 (dd, J=19.3, 7.6 Hz, 2H), 1.44 (s, 9H). MS ES+502.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:9])=[O:8].C([Li])CCC.[CH3:28][C:29]([CH3:31])=[O:30].C(O)(=O)C>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][S:7]([CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:29]([OH:30])([CH3:31])[CH3:28])(=[O:9])=[O:8]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2)c(OC)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(CNS(=O)(=O)C(c2ccccc2)C(C)(C)O)c(OC)c1
Temperature: -78 °C

Procedure:
Under inert gas, 2.00 g of N-(2,4-dimethoxybenzyl)-C-phenylmethanesulfonamide were initially charged in 40 ml of THF, and then, at a temperature of −78° C., 9.54 ml of a 1.5 N butyllithium solution in hexane were added dropwise and the mixture was left to stir while cooling with ice for 5 minutes. Subsequently, the reaction solution was cooled again to −78° C. and a solution of 2.01 ml of acetone in 4 ml of THF was added. The mixture was allowed to come to room temperature and stirred for 30 minutes. The reaction solution was admixed with 0.82 ml of acetic acid and 50 ml of ethyl acetate, and washed with 30 ml of a saturated aqueous sodium hydrogencarbonate solution and 30 ml of a saturated aqueous sodium chloride solution, and the organic phase was dried over Na2SO4 and concentrated by rotary evaporation. The residue (2.67 g) was used in the next reaction without further purification.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:37])=[C:22]([C:24]([C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][CH3:35])=[CH:28][C:27]=2[F:36])=O)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.C(#N)C>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:37])=[C:22]([CH2:24][C:26]2[CH:31]=[C:30]([F:32])[C:29]([O:33][CH2:34][CH3:35])=[CH:28][C:27]=2[F:36])[CH:23]=1
Reactant: CCOc1cc(F)c(C(=O)c2cc(Br)ccc2Cl)cc1F
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CCOc1cc(F)c(Cc2cc(Br)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
Then, Et3SiH (5.93 mL, 0.0371 mol) and BF3.Et2O (2.83 mL, 0.0224 mol) were added sequentially to a chloroform-acetonitrile (1:1; 60 mL) solution of (5-bromo-2-chlorophenyl)(4-ethoxy-2,5-difluorophenyl)methanone (5.58 g, 0.0149 mol) at 4° C. The reaction mixture was warmed to room temperature, stirred for 12 hours and stirred at 45° C. for further three hours. After the reaction mixture was added with a saturated sodium carbonate aqueous solution and extracted with chloroform, the organic layer was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain a colorless oily title compound (3.8 g, 71%).
Reaction SMILES: C(NC(=O)NC1C=CC(C2N=C(N3CCOC[C@@H]3C)C3CCN(C(OC(C)(C)C)=O)CC=3N=2)=CC=1)C.Cl[C:38]1[N:39]=[C:40]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]2[CH3:58])[C:41]2[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=2[N:43]=1.CC1(C)C(C)(C)OB([C:67]2[CH:72]=[CH:71][C:70]([NH:73][C:74](=[O:80])[NH:75][CH2:76][C:77]([NH2:79])=[O:78])=[CH:69][CH:68]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:79][C:77](=[O:78])[CH2:76][NH:75][C:74](=[O:80])[NH:73][C:70]1[CH:69]=[CH:68][C:67]([C:38]2[N:39]=[C:40]([N:52]3[CH2:57][CH2:56][O:55][CH2:54][C@@H:53]3[CH3:58])[C:41]3[CH2:46][N:45]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][C:42]=3[N:43]=2)=[CH:72][CH:71]=1
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(N)=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCC(N)=O)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 12 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)acetamide as starting materials, and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (high pH) yielding the title compound (10.6 mg, 0.02 mmol, 12%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC(OCC(C)C)=O.[NH2:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].Cl>C(Cl)Cl.CN1CCOCC1.O>[O:25]=[C:24]1[C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:22]=2[N:21]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[O:12]1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nc2c(C(F)(F)F)cccc2c(=O)o1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A mixture of 17.5 g of N-BOC glycine, 100 ml of methylene chloride and 13.7 ml of N-methyl-morpholine was cooled to -20° C. and a solution of 13 ml of isobutyl chloroformate in 50 ml of methylene chloride was added. After stirring for 30 minutes at -20° C., a solution of 10.25 g of 2-amino-3-trifluoromethyl benzoic acid [prepared by the process of J. Med. Chem., Vol. 16 (2) 101,6 (1973)] in 5.49 ml of N-methyl-morpholine and 120 ml of methylene chloride was added thereto and after stirring for 20 hours at ambient temperature, the mixuture was poured into 500 ml of water and 150 ml of 2N hydrochloric acid. The mixture was extracted with methylene chloride and the organic phase was washed with water, dried and concentrated under reduced pressure to dryness. The residue was triturated with 50 ml of methanol and the mixture was frozen, separated, washed with methanol and dried under reduced pressure at 50° C. to obtain 11 g of 1,1-dimethylethyl [(4-oxo-8-(trifluoromethyl)-4H-3,1-benzoxazin-2-yl)-methyl]-carbamate melting at 176° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:14][CH:13]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:12]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][N:11]1[CH2:12][CH:13]([CH2:15][CH:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[OH:17])[CH2:14]1
Reactant: O=C(CC1CN(CCc2ccc(F)cc2F)C1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CC1CN(CCc2ccc(F)cc2F)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}-1-phenylethanone (Example 20, 41 mg, 0.117 mmol) in methanol (1 mL) under nitrogen was added sodium borohydride (8.8 mg, 0.23 mmol). The reaction was stirred at room temperature overnight. More sodium borohydride (5 mg, 0.13 mmol) was added and the reaction stirred for 30 minutes. More sodium borohydride (8.8 mg, 0.23 mmol) was added and the reaction stirred for 15 minutes. More sodium borohydride (5 mg, 0.13 mmol) was added and the reaction stirred overnight. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica, eluting with 10% methanol/dichloromethane, to give the title compound. 1H NMR (360 MHz, CDCl3) δ 7.35–7.29 (5H, m), 7.22–7.16 (1H, m), 6.81–6.73 (2H, m), 4.71 (1H, dd, J=5.3, 7.6 Hz), 3.63 (1H, s), 3.53 (1H, s), 3.11 (1H, s), 2.98 (1H, s), 2.77 (5H, s), 2.07–1.92 (2H, m); m/z (ES+) 318 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N:22]([O-])=O.[Na+].[I-].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:22]=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)ccc1Nc1ccc(F)cc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(-n2nnc3cc(Br)ccc32)cc1
Reaction time: 0.33 h
Yield: 89 %

Procedure:
To a stirred room temperature solution of 4-bromo-N1-(4-fluorophenyl)benzene-1,2-diamine (1.4 g, 5 mmol) in DMSO (12 mL), was added 30% sulfuric acid (12 mL). The mixture was then cooled (ice-bath) and a solution of sodium nitrite (380 mg, 5.5 mmol) in water (1 mL) was added dropwise. After 20 minutes, a solution of sodium iodide (2.4 g, 15.8 mmol) in water (2 mL) was added dropwise and the cold bath was removed. After 30 minutes, LCMS showed only a single product [MS m/z 292/294 (MH+)] consistent with the desired product. The mixture was poured into 150 mL of ice water and the resulting precipitate was filtered, washed with sodium thiosulfate solution, water and dried to afford 1.3 g of 5-bromo-1-(4-fluorophenyl)-1H-benzotriazole as a light purple solid. MS m/z 292/294 (MH+).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: FC(F)(F)c1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 3-iodo-5-(trifluoromethyl)-1H-indazole (4.0 g, 12.8 mmol) in THF (80 mL) was added t-BuOK (2.0 g, 17.9 mmol) slowly at 0° C. and mixture stirred for 30 minutes, iodomethane (1.1 mL, 17.9 mmol) was added at 0° C., then warmed to room temperature and stirred for 1.5 hours, quenched with water (30 mL) and extracted with EtOAc (3×30 mL), the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with ether (5 mL) and filtered to give 3-iodo-1-methyl-5-(trifluoromethyl)-1H-indazole (3.3 g, 79.3%) as a white solid. LCMS: (M+H)+=327.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[C:4]([F:14])[C:3]=1[F:15].C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([F:14])[C:3]=1[F:15]
Reactant: CCOC(=O)Cc1ccc(N)c(F)c1F
Reactant: Cc1ccccc1N=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)c(F)c1F
Reaction time: 48 h
Yield: 41.6 %

Procedure:
To a stirred solution of ethyl 4-amino-2,3-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF—MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,3-difluorophenylacetic acid (200 mg, 42%) as a white solid. 1H-NMR (CDCl3) δ2.30 (s, 3H), 3.35 (s, 2H), 6.98 (m, 1H), 7.04 (m, 1H), 7.18 (d, J=7.3 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.90 (m, 1H); MS FAB) m/z 321 (M++1).