Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([O:33]COC)=[CH:29][CH:28]=3)([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[OH:20])[CH:8]=2)[N:3]=1.[ClH:37]>CO>[Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([OH:20])([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[CH:8]=2)[N:3]=1.[ClH:37]
Reactant: COCOc1ccc(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(C(O)(c2cccnc2)c2ccc3nc(Cl)c(-c4ccccc4)c(Cl)c3c2)cc1

Procedure:
(2,4-Dichloro-3-phenylquinolin-6-yl)[4-(methoxymethoxy)phenyl]pyridin-3-ylmethanol (20 mg, 0.039 mmol, Example 23) in MeOH (2 mL) was treated with 37% HCl (1 mL) at room temperature for 18 hours, and concentrated. The residue was purified by reverse phase HPLC (water/acetonitrile/0.1% TFA) to give the title compound as an off-white solid. 1H NMR (400 MHz, MeOH-d4) δ 8.85 (d, J=2.20 Hz, 1H), 8.75 (d, J=4.89 Hz, 1H), 8.48 (dt, J=1.80, 8.13 Hz, 1H), 8.31 (d, J=1.96 Hz, 1H), 8.02 (d, J=9.05 Hz, 1H), 7.95 (dd, J=5.62, 8.31 Hz, 1H), 7.86 (dd, J=1.96, 8.80 Hz, 1H), 7.48-7.57 (m, 3H), 7.33 (dd, J=1.47, 7.83 Hz, 2H), 7.08-7.16 (m, 2H), 6.77-6.84 (m, 2H); MS m/e 473.0 [M+H]+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][N:18]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2[CH:27]=O)=[N:19]1.O>O1CCCC1>[CH3:17][N:18]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[C:24]2/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1cc2c(C=O)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.4 %

Procedure:
Under nitrogen atmosphere, to a suspension of sodium hydride (1.26 g, 31.5 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (7.06 g, 31.5 mmol) in tetrahydrofuran (50 mL) at 0° C., and the mixture is was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl-2H-indazole-4-carbaldehyde (4.60 g, 28.7 mmol) in tetrahydrofuran (100 mL), and the mixture was warmed to room temperature over 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.50 g, yield 98%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([OH:10])[C:4]([CH3:12])([CH3:11])[CH2:3]1.OO.[OH2:15]>C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[OH:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:3][C:4]([OH:15])([CH3:12])[CH3:11])[C:4]([CH3:12])([CH3:11])[CH2:3]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: CC(C)(C)O
Product: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 9 %

Procedure:
A solution of 0.25 g (1.0 mmol) of copper(II) sulfate pentahydrate in 5 mL of water is added to a solution of 0.16 g (1.0 mmol) of 2,2'-dipyridyl in 120 mL of tert-butyl alcohol. To this solution is added 8.6 g (50 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine. A solution of 13.6 g (200 mmol) of 50% aqueous hydrogen peroxide mixed with 13 mL of tert-butyl alcohol is added dropwise to the reaction mixture at 23-40° C. over three hours. The mixture is then stirred at ambient temperature for 72 hours. Gas chromatography shows 9% of the title compound is present in the reaction mixture.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C(OCC)C.C([Li])CCC.C(O[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1)(C)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
4-bromobenzotrifluoride (4.8 g, 21.3 mmol) was placed in a reaction flask. To ensure a nitrogen atmosphere in the reaction flask, the gas in the reaction flask was drawn out and the reaction flask was refilled with nitrogen gas in a rapid manner three times. To the reaction flask, 50 ml of anhydrous diethylether was added, and then 10 ml of n-butyllithium solution (25.6 mmol, 2.5 M in n-hexane) was slowly added at −78° C. to obtain a mixture. In the meanwhile, the color of the mixture changed from transparent to cloudy green. The mixture was kept at −78° C. and continuously stirred for 60 minutes. Next, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.2 ml, 25.6 mmol) was slowly added to the mixture at −78° C., and then the temperature was slowly raised to and kept at 20° C. for 12 hours for reaction. The color of the mixture in the reaction flask changed from cloudy green to cloudy white. Deionized water was slowly added to the mixture to terminate the reaction in the reaction flask. The solvents in the mixture were drawn out of the reaction flask, and the residue in the reaction flask was washed several times with ethyl acetate and with a saturated sodium chloride solution to collect an organic layer, followed by dehydration of the organic layer using sodium sulfate (Na2SO4) to thereby obtain a crude product. The crude product was recrystallized in a mixed solvent having dichloromethane and n-hexane (dichloromethane:n-hexane=1:1) at 20° C., thereby obtaining white crystals (4.27 g, 73% yield).
Reaction SMILES: [H-].[Na+].[CH:3](=[C:10]1/[C:11](=[O:29])[NH:12][C:13](=[O:28])/[C:14]/1=[CH:15]/[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:30][O:31][CH2:32]Cl>CN(C)C=O>[CH3:30][O:31][CH2:32][N:12]1[C:13](=[O:28])/[C:14](=[CH:15]/[C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)/[C:10](=[CH:3]\[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:11]1=[O:29]
Reactant: COCCl
Reactant: COc1cc(/C=C2/C(=O)NC(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN1C(=O)C(=C/c2ccccc2)/C(=C\c2cc(OC)c(OC)c(OC)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a suspension of 63.2% sodium hydride (0.38 g) in dimethylformamide (10 ml) is added dropwise a solution of (3E,4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.65 g) in dimethylformamide (10 ml) under ice-cooling, and the mixture is stirred at room temperature for one hour. To the mixture is added dropwise methoxymethyl chloride (0.84 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and to the residue is added ethyl acetate. The mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; n-hexane:trichloromethane:ethyl acetate=5:5:4) to give (3E,4E)-1-methoxymethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.0 g) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:7]=1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Reactant: OCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 303 (M+, 52), 302 ([M—H]+, 74), 286 (30), 108 (100), 92 (63), 65 (52).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[CH:12].N>>[C:13]1([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: ON=C(Cl)c1cnccn1
Agent: N
Product: c1ccc(-c2cc(-c3cnccn3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 1-ethynyl-benzene (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.41 (s, 1H), 7.47-7.70 (m, 3H), 7.86-8.08 (m, 2H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.8, 1.6 Hz, 1H), 9.29 (d, J=1.2 Hz, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[N+:18]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N(C)C
Agent: [Pd]
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)C

Procedure:
The title compound was prepared from (5-dimethylamino-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example C19) (3.22 g, 10.9 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a gray solid (2.05 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH3:16])[CH:10]([NH:17]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:24])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH3:16])[CH:10]([NH2:17])[CH2:9][CH2:8]1)=[O:47]
Reactant: CCOC1CCN(c2c(N)cnn2C)CCC1NC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: CCOC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)CCC1N
Yield: 60 %

Procedure:
Following the procedure for Example 107, starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-ethoxyazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 385 as a brown solid (127 mg, 60% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.85 (s, 1H), 7.42-7.28 (m, 1H), 7.04 (t, J=8.9 Hz, 2H), 6.19 (s, 2H), 3.78-3.58 (m, 4H), 3.47-3.35 (m, 1H), 3.38-3.25 (m, 2H), 3.25-3.16 (m, 3H), 3.09-3.01 (m, 1H), 2.13 (d, J=14.7 Hz, 1H), 2.00 (d, J=14.7 Hz, 1H), 1.92-1.82 (m, 1H), 1.84-1.58 (m, 3H), 1.22 (t, J=7.0 Hz, 3H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].Cl.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CNCCC(O)c1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CNCCC(Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a cooled suspension of 20 g of γ-hydroxy-N-methylphenylpropylamine.HCl in chloroform are added dropwise 30 ml of thionylchloride. The mixture is subsequently stirred at room temperature till all solid substance has been dissolved. The solvent chloroform and the excess of thionylchloride are distilled off after which the residue is washed with ether and then made alkaline (pH=8) with a sodiumcarbonate solution (10%). The alkaline solution is subsequently extracted with ether and the ether extracts washed with water, dried and evaporated to dryness. The residue (oil) is used without any additional purification (yield 15.6 g; 85%).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>CCO.[Pd]>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 99.9 %

Procedure:
A solution of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method. The reaction mixture was filtered through celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].[Cl-].[Na+]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][C:10]1([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:12][CH2:13]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(COCc2ccccc2)CCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(COCc2ccccc2)CCC1
Reaction time: 2 h

Procedure:
To a solution of 12.0 g (59.0 mmol) of {1-[(benzyloxy)methyl]cyclobutyl}methanol in 180 mL of dichloromethane was added 9.93 ml (70.8 mmol) of triethylamine at 0° C. followed by the addition of 5.02 mL (64.9 mmol) of methanesulfonyl chloride. After stirring for 2 h, saturated sodium chloride solution was added. The organic phase was isolated, dried using magnesium sulfate, and concentrated under vacuum to afford the crude product, which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 7.39-7.32 (m, 5H), 4.57 (s, 2H), 4.30 (s, 2H), 3.52 (s, 2H), 2.98 (s, 3H), 1.95 (m, 6H).
Reaction SMILES: Cl[C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41].CN(C)CCCNC1N=C2C(C3C=CC=C(C(F)(F)F)C=3)=C(C)C(C3N(C4C=CC(C#N)=CC=4)N=CC=3)=CN2N=1>>[CH3:35][N:36]([CH3:42])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(Cl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCCN
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NCCCCN(C)C)nc2c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 4-{5-[2-chloro-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Int. 19, 93 mg, 0.19 mmol) and N,N-dimethyl-butane-1,4-diamine (1.0 mL) using a similar method to that used in Example 28 (47 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21](B2OCC(C)(C)CO2)[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O.[Pd](Cl)Cl.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[C:25]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:26]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: CC1(C)COB(c2cc(Cl)ccc2C#N)OC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(Cl)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 5.8 %

Procedure:
A solution of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (200 mg, 0.68 mmol), 4-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (205 mg, 0.816 mmol), cesium carbonate (0.22 g, 0.68 mmol) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) palladium dichloride (24.0 mg, 0.05 eq) in a mixture of acetonitrile and water (10 mL, 10:1) was purged with nitrogen and stirred at 90° C. for 45 minutes under microwave irradiation. Ethyl acetate (20 mL) was added to the reaction mixture and it was filtered. The solid was extracted with ethyl acetate (20 mL×4). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by HPLC separation to give the product (13.7 mg, 5.8%). LCMS (ESI): RT (min)=1.099, M+H+=347.9, method=A. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.24 (s, 1H), 8.54 (s, 1H), 8.33 (t, J=0.8 Hz, 1H), 8.08-7.72 (m, 5H), 2.09-2.05 (m, 1H), 0.88-0.83 (m, 4H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[OH-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:15]=1[CH2:16]Br>C(O)C>[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH2:16][C:15]2[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=2[F:22])[N:4]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1cccc(F)c1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(O)nc(SCc2c(F)cccc2F)n1
Temperature: 22 °C

Procedure:
4-Amino-6-hydroxy-2-mercaptopyrimdine monohydrate (1.61 g, 10.0 mmol) is suspended in 50% ethanol (10 ml), then treated with solid sodium hydroxide (440 mg, 11.0 mmol) and stirred until the solid dissolved. 2,6-Difluoro-benzyl bromide (2.17 g, 10.5 mmol) is added and the reaction heated to reflux for 1.5 hrs. After cooling to 22° C., the solid is collected, washed with water, then air dried. The title compound is recrystallized from ethanol, mp 245-246° C.
Reaction SMILES: [I-:1].[Na+].[C:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH2:5][CH2:6]Cl>C(#N)C>[C:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([I:1])[CH3:6]
Reactant: [I-]
Reactant: CC(C)OC(=O)OCCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)OC(=O)OC(C)I
Temperature: 60 °C
Yield: 68.6 %

Procedure:
Sodium iodide (20.69 g, 138.0 mmol) was added to the crude solution of chloroethyl isopropyl carbonate (5.11 g, 30.67 mmol) in acetonitrile (50 mL). The resulting mixture was heated to 60° C. for 2 hours and then allowed to cool to 25° C. The reaction mixture was concentrated under reduced pressure and the resulting mixture was treated with diethyl ether. The solids were filtered off and the filtrate was concentrated under reduced pressure to obtain 1-iodoethyl isopropyl carbonate as a dark orange oil (5.43 g, 69% yield).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a stirred solution of methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (0.3 g, 0.72 mmol) in methanol/THF (2/2, 4 mL) was added LiOH (0.122 g, 2.9 mmol) in H2O (4 mL) and the reaction mixture was stirred at rt for 2 h. It was concentrated under reduced pressure. the residue was diluted with water (2 mL) and was extracted with dichloromethane (5 mL). The aqueous layer was separated and was acidified with 1.5 N HCl (pH ˜5-6) to get a white precipitate, which was collected by filtration and dried under vacuum to give 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.2 g 69%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClC1C=C(C=CN=1)C(O)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:26]=[C:27]3C4(CCNCC4)C[N:31](C(OCC4C=CC=CC=4)=O)[C:28]3=[CH:29][CH:30]=2)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C=O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:26]=[CH:27][C:28]([NH2:31])=[CH:29][CH:30]=2)=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)N1CC2(CCNCC2)c2cc(Sc3ccc(F)cc3)ccc21
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(Sc2ccc(F)cc2)cc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
Oxalyl chloride (1.68 mL, 19.59 mmol) and a catalytic amount of N,N-dimethylformamide are added to a pre-cooled (0° C.) suspension of 2-chloroisonicotinic acid (1.032 g, 6.55 mmol) in dichloromethane (350 mL). After the gas evolution ceases, the mixture is allowed to reach room temperature and is stirred for 1 h. The volatiles are then removed under reduced pressure. The residue obtained is dissolved in dichloromethane (150 mL) and the resulting solution is added to a pre-cooled (0° C.) solution of crude benzyl 5-(4-fluorophenylthio)spiro[indoline-3,4′-piperidine]-1-carboxylate (3.50 g, 42% wt/wt, 3.25 mmol) and N,N-diisopropylethylamine (1.65 mL, 9.64 mmol) in dichloromethane (400 mL). The reaction is stirred for 45 min at room temperature until complete conversion of the starting material is observed. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate (100 mL) and with brine (100 mL). The organic layer is dried over sodium sulphate, is filtered and is concentrated under reduced pressure. The yellow oil isolated is purified by column chromatography on silica gel (heptane/ethyl acetate 25 to 50% as eluent) to afford the desired product (1.58 g, 2.69 mmol, 83% yield) (HPLC-MS Method 2: retention time: 2.268 min, m/z 588.0).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[C:6]([CH3:15])=[CH:5][C:4]1([CH3:17])[CH3:16])[CH3:2].[BrH:18]>C(O)(=O)C>[BrH:18].[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:15])=[CH:5][C:4]1([CH3:16])[CH3:17])[CH3:2]
Reactant: CCN1c2cc(OC)ccc2C(C)=CC1(C)C
Agent: Br
Solvent: CC(=O)O
Product: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Yield: 85 %

Procedure:
60 g (0.25 mol) N-ethyl-2,2,4-trimethyl-7-methoxy-1,2-dihydroquinoline was dissolved in 150 ml glacial acetic acid and 150 ml hydrobromic acid was added. The solution was refluxed for 24 h. The cooled solution was stirred in an ice/methanol bath. Subsequently the precipitate was filtered and washed several times with acetone. Colourless crystals were formed in a yield of 85%.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([O:21]CC)=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1.[Li+].[OH-]>>[CH3:1][C:2]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:19]([OH:21])=[O:20])[CH:11]([C:15]([F:18])([F:17])[F:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)C1=Cc2ccc(Cc3ccc(C)cc3C)cc2OC1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccc(Cc2ccc3c(c2)OC(C(F)(F)F)C(C(=O)O)=C3)c(C)c1
Temperature: 40 °C
Yield: 93 %

Procedure:
The ester from Example 9s, Step 5 was added THF(7): EtOH(2): H2O(1) followed by LiOH (1.5 eq) and heated to 40° C. for 4 h. The reaction was cooled to room temperature, concentrated in vacuo. Acidified with HCl conc to pH 1, filtered solid and subjected solid to preparative reverse phase chromatography to produce the title compound (93%): ESHRMS m/z 361.1062 (M−H, C20H16O3F3Calc'd 361.1046). 1HNMR (DMSO-d6/400 MHz), 13.19 (s, 1H), 7.77 (s, 1H), 7.33 (d, 1H, J=7.6 Hz), 7.00 (m, 3H), 6.77 (d, 1H, J=7.7 Hz), 6.70 (s, 1H), 5.82 (q, 1H, J=7.1 Hz), 3.87 (s, 2H), 2.2 (s, 3H), 2.10 (s, 3H).