Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([NH:7][N:8]=[C:9]([C:11]1[C:15]([OH:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[S:13][CH:12]=1)[CH3:10])=[O:6].CC(C)([O-])C.[Na+].C1N=CN([C:40](N2C=NC=C2)=[S:41])C=1.Cl>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:14]2[S:13][CH:12]=[C:11]([C:9](=[N:8][NH:7][C:5]([C:4]3[CH:25]=[CH:26][C:27]4[NH:28][C:40](=[S:41])[NH:1][C:2]=4[CH:3]=3)=[O:6])[CH3:10])[C:15]=2[OH:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(=NNC(=O)c1ccc(N)c(N)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc2[nH]c(=S)[nH]c2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of 3,4-diamino-N′-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl}ethylidene]benzohydrazide(30 mg, 0.064 mmol, see the synthetic example 176) in tetrahydrofuran (3.0 mL) was added sodium tert-butoxide (12 mg, 0.13 mmol) and N,N′-thiocarbonyldiimidazole (23 mg, 0.13 mmol). The reaction mixture turned clear orange and was stirred at room temperature for 16 hours, and then was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. The precipitated solid was collected by filtration, washed with chloroform, washed with methanol and dried by means of a vacuum pump to give the desired product as a pale brown solid (yield 52%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][N:15]1[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16]1=[O:17])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: OCc1cccc(OCc2ccccc2)c1
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc(OCc2ccccc2)c1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with the methanesulfonate ester of 3-benzyloxybenzyl alcohol, in 67% overall yield as a viscous liquid, after flash chromatography eluting with 30-100% EtOAc in hexane, IR (CHCl3) 3434, 2933, 1681, 1500, 1401, 1256, 1054, 751 cm-1 ; 1H NMR (CDCl3) δ 1.77 (br s, 1H plus HDO), 2.20-2.34 (m, 2H), 3.91 (t, J=5.5 Hz, 2H), 4.82 (dd, J=7.5, 5.7 Hz, 1H), 5.02 (s, 2H), 5.11 (ABq, JAB =16.0 Hz, 2H), 6.85-7.01 (m, 7H), 7.22-7.41 (m, 6H); MH+ at m/z=390; Anal. Calc'd for C24H23NO4 : C, 74.02; H, 5.95; N, 3.60. Found: C, 73.61; H, 6.03; N, 3.55.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:13]=O)[N:10]([CH3:12])[N:11]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:27](I)=[CH:26][N:25]([Si](C(C)C)(C(C)C)C(C)C)[C:22]2=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:27]2[C:21]3[C:22](=[N:23][CH:24]=[C:19]([F:18])[CH:20]=3)[NH:25][CH:26]=2)[N:10]([CH3:12])[N:11]=1
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(F)cnc21
Product: Cn1nc(NCc2cccc(Cl)c2)cc1Cc1c[nH]c2ncc(F)cc12

Procedure:
(3-Chloro-benzyl)-[5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-1-methyl-1H-pyrazol-3-yl]-amine P-2006 was prepared in two steps from 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde 145 and 5-fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 146 as shown in Scheme 18.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1cccc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cccc(Cl)c3)cc2)c1C
Yield: 26.2 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(3-chlorophenylsulfanyl)-benzene (0.159 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.065 g, 26%) as a solid.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Cl:13][C:10]1[CH:11]=[N:12][C:2]([CH3:14])=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(Cl)cnc1Cl
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(Cl)cnc1C
Temperature: 25 °C
Yield: 37958.3 %

Procedure:
A mixture of ethyl 2,5-dichloronicotinate (step 1, 10 g, 0.045 mol), tetrakis(triphenylphoshine)palladium (5.2 g, 4.5 mmol), trimethylboroxine (5.65 g, 0.045 mmol) and potassium carbonate (18.66 g, 0.16 mmol) in 1,4-dioxane (contain 10% water, 100 ml) was refluxed for 7 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (50/1 to 20/1) to afford 3.41 g (38%) of the title compound:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[C:8]([C:11]1[CH:12]=[C:13]([CH:17]2[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:29](O)=[O:30])[CH:23]=3)[NH:18]2)[CH:14]=[CH:15][CH:16]=1)(=[O:10])[NH2:9].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:1][S:2]([NH:5][C:29]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:8]([NH2:9])=[O:10])[CH2:26][C:25]2([CH3:28])[CH3:27])=[O:30])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(C(N)=O)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a suspension of methanesulfonamide (160 mg, 1.65 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (66 mg, 1.65 mmol). The resulting mixture was stirred at 25° C. for 1 h to afford Solution A32. A solution of 2-(3-carbamoyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.33 mmol) and 1,1′-carbonyldiimidazole (110 mg, 0.66 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B32. Solution B32 was added to Solution A32 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 3-(6-methanesulfonylaminocarbonyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-benzamide (13 mg, 10%) as a white solid: MS (ESI) M+1=402.3.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](S(C)(=O)=O)[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2].[CH2:16]([NH2:18])[CH3:17]>C1COCC1.O>[CH2:1]([C:3]1[N:8]=[C:7]([NH:18][CH2:16][CH3:17])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH3:2]
Reactant: CCN
Reactant: CCc1cc(C(=O)O)nc(S(C)(=O)=O)n1
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(CC)cc(C(=O)O)n1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid (325 mg, 1.41 mmol) in THF (5 mL) is added 70% ethylamine in water (2.0 mL). The mixture is stirred at 70° C. overnight. It is then evaporated to dryness and purified by prep. TLC (DCM/7N NH3 in MeOH 4/1) to give 6-ethyl-2-ethylamino-pyrimidine-4-carboxylic acid as a yellow oil (200 mg); LC-MS: tR=0.58 min, [M+H]+=194.07. 1H NMR (CDCl3): δ 1.34 (m, 6H), 2.84 (d, J=7.5 Hz, 2H), 3.64 (m, 2H), 7.26 (s, 1H), 11.0 (s br, 1H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][C@@H:28]([N+:32]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=2)([CH3:34])[CH3:33])[CH2:29][CH2:30][CH3:31])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1.[CH2:45]1[O:47][C@H:46]1[CH2:48][OH:49]>CCO>[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[NH2:15][C:16]1[C:17]([C:24]([NH:26][CH2:27][C@@H:28]([N+:32]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][OH:49])=[CH:40][CH:39]=2)([CH3:34])[CH3:33])[CH2:29][CH2:30][CH3:31])=[O:25])=[N:18][C:19]([Cl:23])=[C:20]([NH2:22])[N:21]=1
Reactant: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(O)cc1
Reactant: OC[C@H]1CO1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC[C@@H](CNC(=O)c1nc(Cl)c(N)nc1N)[N+](C)(C)CCCc1ccc(OC[C@@H](O)CO)cc1

Procedure:
Triethylamine (63.5 μL, 0.46 μmol) is added to a solution of ((S)-1-{[(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-butyl)-[3-(4-hydroxy-phenyl)-propyl]-dimethyl-ammonium trifluoroacetate (Example 121)(50 mg, 0.091 mmol) in EtOH (5 mL) and the solution is heated to reflux. Once at reflux (S)-glycidol (6.04 μL, 0.091 mmol) is added and the reaction is heated at reflux overnight. Two further portions of (S)-glycidol (2×6.04 μl, 2×0.091 mmol) are added and the reaction is heated at reflux for 24 h. The reaction mixture is concentrated in vacuo and purification by reverse phase chromatography (Isolute™ C18, 0-30% acetonitrile in water with 0.1% TFA) affords the title compound. M+ 509. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (1H, t), 8.20-7.18 (2H, br), 7.24-6.98 (2H, br), 6.99 (2H, d), 6.79 (2H, d), 5.70-3.98 (2H, br), 3.93-3.89 (1H, m), 3.85-3.67 (3H, m), 3.60-3.43 (3H, m), 3.42 (2H, d), 3.39-3.28 (1H, m), 3.04 (3H, s), 3.01 (3H, s), 2.48-2.32 (2H, m), 2.00-1.71 (3H, m), 1.61-1.37 (3H, m), 0.91 (3H, t).
Reaction SMILES: [CH3:1][S:2][C:3]([CH3:19])([CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([OH:15])=[O:14].[CH:20]1[CH:25]=CC=C[CH:21]=1.C(Cl)(=O)C(Cl)=O.C(=O)(O)[O-].[Na+]>CCOCC.C(O)(C)C>[CH3:1][S:2][C:3]([CH3:18])([CH3:19])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:17])[CH2:8][CH:9]=[CH:10][C:11]([CH3:16])=[CH:12][C:13]([O:15][CH:20]([CH3:25])[CH3:21])=[O:14]
Reactant: c1ccccc1
Reactant: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOCC
Product: CSC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C
Reaction time: 2 h

Procedure:
To 0.6 g. of 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoic acid in 10 ml. of dry benzene is added 0.23 ml. of oxalyl chloride at room temperature with stirring. After 2 hours, isopropanol (2ml.) is added and the mixture allowed to stand at room temperature for about 2 hours. Ether and saturated sodium bicarbonate is added and the organic phase separated. The organic phase is washed with aqueous sodium bicarbonate, saturated sodium chloride, dried over calcium sulfate and evaporated to yield isopropyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].I[CH3:19]>C(Cl)(Cl)Cl.[Ag]=O>[CH3:19][O:17][CH2:16][C:12]1[C:9]2[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:7][C:8]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc2cccc(COC)c2c1C
Temperature: 55 °C
Yield: 93.8 %

Procedure:
To a solution of 0.19 g (0.81 mmole) of ethyl 4-(hydroxymethyl)-3-methyl-1-benzofuran-2-carboxylate (Example 92, Step 2) in 2 mL of chloroform was added silver (II) oxide (0.34 g, 1.46 mmol, 1.8 eq) and 2 mL of iodomethane and the mixture was heated in sealed tube at ˜55° C. for 4.5 days. The reaction was filtered and concentrated in vacuo to provide 0.20 g of ethyl 4-(methoxymethyl)-3-methyl-1-benzofuran-2-carboxylate. Yield: ˜93.8% m.p. 45-47° C.; MS: 249.1(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]([O:9]CC)=O.[F:18][C:19]([F:24])([F:23])[C:20](N)=[NH:21]>C(O)C>[C:12]1([C:5]2[C:6]3[C:7](=[O:9])[NH:21][C:20]([C:19]([F:24])([F:23])[F:18])=[N:1][C:2]=3[S:3][CH:4]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2scc(-c3ccccc3)c12
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Ethyl 2-amino-4-phenyl-thiophene-3-carboxylate (2 g, 8.087 mmol) and trifluoroacetamidine (4.531 g, 40.44 mmol) were combined in ethanol (20 mL) and heated to reflux overnight. Further trifluoroacetamidine (4.531 g, 40.44 mmol) was added and the reaction heated to reflux for a further 18 hours. The reaction mixture was allowed to cool to room temperature. The resulting precipitate was filtered off, washed with ethanol (5 mL) and dried in vacuo at 40° C. to afford 5-phenyl-2-(trifluoromethyl)-3H-thieno[2,3-d]pyrimidin-4-one (1.195 g). LCMS: purity 99%, RT=4.11 min, M+1=297.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6][N:5]=1)([CH3:3])[CH3:2].[CH3:22]OC1C=C2C(C(C(C)C(O)=O)=CN=C2N2CCOCC2)=CC=1>>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:18][C:19]([OH:21])=[O:20])=[CH:6][N:5]=1)([CH3:22])([CH3:3])[CH3:2]
Reactant: COc1cc2c(CC(=O)O)cnc(C(C)C)c2cc1OC
Reactant: COc1ccc2c(C(C)C(=O)O)cnc(N3CCOCC3)c2c1
Product: COc1cc2c(CC(=O)O)cnc(C(C)(C)C)c2cc1OC

Procedure:
(1-Isopropyl-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid, characterised as the ethyl ester 1H NMR (400 MHz, CDCl3) δ 1.25 (t J 7 3H), 1.45 (d J 7 3H), 3.82 (heptet J 7 1H), 3.90 (s 2H), 3.08 (s 2H), 4.15 (q J 7 2H), 7.28 (s 1H), 7.48 (s 1H), 8.30 (s 1H). Intermediate 41: 2-(7Methoxy-1-morpholin-4-yl-isoquinolin4-yl)-propionic acid mp 225-227° C., is prepared according to the procedure for Intermediate 27.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:32])([F:31])[F:30])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7]>C(O)C.[OH-].[Na+]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:35])[N:25]([CH3:34])[C:26]([CH3:33])=[CH:27][C:28]=2[C:29]([F:31])([F:32])[F:30])=[CH:21][CH:22]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Reaction time: 5 h
Yield: 92.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (177 mg, 0.326 mmol) in ethanol (6 mL) was added IN aqueous sodium hydroxide solution (4 mL) at room temperature. The mixture was stirred for 5 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (20 mL). The aqueous solution was washed with diethyl ether (50 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 159 mg (92% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine as a white solid: mp 238-240° C. ES-HRMS m/e calcd for C24H19Cl2F3N2O4 (M+Na) 549.0567, found 549.0570.
Reaction SMILES: CC([O-])(C)C.[K+].[Si:7]([O:14][CH2:15][CH2:16][N:17]1[C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[CH2:19][C:18]1=[O:32])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[N:33](OCCC(C)C)=[O:34]>O1CCCC1>[Si:7]([O:14][CH2:15][CH2:16][N:17]1[C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]2[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=2[C:19](=[N:33][OH:34])[C:18]1=[O:32])([C:10]([CH3:13])([CH3:11])[CH3:12])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCN1C(=O)Cc2ccccc2-c2cccnc21
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCn1c(=O)c(=NO)c2ccccc2c2cccnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
Add potassium 2-methylpropan-2-olate (66.1 g, 588.8 mmol) to a solution of 5-[2-(tert-butyl(dimethyl)silyl)oxyethyl]-7H-pyrido[2,3-d][3]benzazepin-6-one (155.0 g, 420.6 mmol) in tetrahydrofuran (1.6 L) at −5° C. and stir for 10 minutes. Add isoamyl nitrite (61.9 mL, 462.6 mmol) dropwise at −5° C. and stir mixture for 10 minutes. Pour over ice/water (2 L) and extract with ethyl acetate (3×200 mL). Wash combined organics with brine (200 mL), dry over sodium sulfate. Add toluene (1 L) and concentrate (×3) to obtain the title compound as a thick brown oil (160.0 g, 402.5 mmol, 96%). MS (m/z): 398 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]([NH2:14])=O)[O:8][C:7]=2[CH:15]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:14])[O:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2c(c1)OC(C(N)=O)=CO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)OC(C#N)=CO2

Procedure:
1.76 g (8.52 mmol) of the amide obtained in Step A and 4.62 g (30 mmol) of phosphorus oxychloride are dissolved in 40 ml of anhydrous pyridine. The reaction medium is then heated at reflux for 1 hour under an inert atmosphere; the solvent is then evaporated in vacuo. The residue obtained is slowly hydrolysed with a saturated solution of sodium hydrogen carbonate; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. The title nitrile is obtained pure in the form of a white solid after passage over a silica column (eluant:AcOEt/PE:10/60).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[N:6]=[C:5]([NH2:22])[N:4]=1.[CH3:23][OH:24]>C(OCC)(=O)C>[F:21][C:17]1[CH:16]=[C:15]([C:7]2[C:8]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)=[C:3]([O:24][CH3:23])[N:4]=[C:5]([NH2:22])[N:6]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1nc(Cl)c(-c2ccncc2)c(-c2cccc(F)c2)n1
Reactant: CO
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1nc(N)nc(-c2cccc(F)c2)c1-c1ccncc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
After sodium (20 mg, 0.870 mmol) was dissolved in methanol (3 ml), 4-chloro-6-(3-fluorophenyl)-5-(4-pyridyl)-2-pyrimidinylamine (50 mg, 0.166 mmol) was added thereto and the mixture was stirred under an atmosphere of nitrogen gas at 60 to 65° C. for 30 minutes. After cooling as it was, the reaction mixture was diluted with ethyl acetate. Then, the mixture was washed with an aqueous ammonium chloride solution thrice and brine, dried over anhydrous sodium sulfate and concentrated. To the residue was added diethyl ether, and the resulting precipitates were collected by filtration and washed with diethyl ether, to give the title compound (16 mg, 32%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](C(O)=O)=[CH:10][C:9]=2[S:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.O>C(CN)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][CH:11]=[CH:10][C:9]=2[S:16][C:17]([F:19])([F:18])[F:20])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(SC(F)(F)F)c(-c2ccc(Cl)cc2)[nH]1
Solvent: NCCO
Solvent: O
Product: FC(F)(F)Sc1cc[nH]c1-c1ccc(Cl)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 25.6 %

Procedure:
A mixture of 5-(p-chlorophenyl)-4-[(trifluoromethyl)thio]pyrrole-2-carboxylic acid (0.5 g, 0.00155 mol) in ethanolamine (1.5 mL) is stirred at 160° C. for five hours, cooled to room temperature overnight with stirring, poured into water and extracted with ether. The combined organic extracts are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow syrup. Flash chromatography of the syrup using silica gel and a 1:4 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.11 g, mp 59°-64° C.) which is identified by 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH2:13]([CH:15]1[O:17][CH2:16]1)[Cl:14]>CCOCC>[CH2:1]([O:8][CH2:16][CH:15]([OH:17])[CH2:13][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: ClCC1CO1
Agent: FB(F)F
Solvent: CCOCC
Product: OC(CCl)COCc1ccccc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A 1,000 mL, 3-necked flask equipped with a mechanical stirrer, condenser, thermometer and 500 mL addition funnel was charged with benzyl alcohol (324 g, 3.0 mol) and 5% BF3 -etherate in ether (10 mL). This mixture was stirred and heated to 80° C. Epichlorohydrin (278 g, 3.0 mol) was added dropwise over 6 hours, and the reaction mixture was stirred an additional 24 hours at 80° C. The crude product was distilled from NaHCO3 (1 g) using a 25 cm Vigreux column. The fractions boiling from 95° C. (0.05 mm) to 120° C. (0.03 mm) were collected and combined to yield 353 g (58%) of pure 3-benzyloxy-2-hydroxypropyl chloride.