Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([CH:4]1[CH2:8][N:7]([C:9]([NH:11][CH2:12][CH3:13])=[NH:10])[N:6]=[CH:5]1)[CH3:3].CCN(C(C)C)C(C)C.[N:23]1[S:27][N:26]=[C:25]2[C:28]([S:32](Cl)(=[O:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:24]=12>C(Cl)Cl>[CH2:12]([NH:11][C:9]([N:7]1[CH2:8][CH:4]([CH2:2][CH3:3])[CH:5]=[N:6]1)=[N:10][S:32]([C:28]1[C:25]2=[N:26][S:27][N:23]=[C:24]2[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])[CH3:13]
Reactant: CCNC(=N)N1CC(CC)C=N1
Reactant: O=S(=O)(Cl)c1cccc2nsnc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc2nsnc12)N1CC(CC)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
300 mg 4,N-Diethyl-4,5-dihydro-pyrazole-1-carboxamidine hydrochloride was suspended in 10 mL DCM. 0.53 mL DiPEA and 310 mg benzo[1,2,5]thiadiazole-4-sulfonylchloride were added and the mixture was stirred overnight at room temperature. The mixture was washed with 5% NaHCO3 and 2 M NaOH, the organic layer dried over Na2SO4 and the solvent evaporated in vacuo to yield 410 mg of a red/brown oil. The crude product was purified by flash chromatography (DCM:aceton=98:2, Rf=0.18) to yield 350 mg (65%) of an orange oil. 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=7.5 Hz, 3H), 1.16 (br t, J=7 Hz, 3H), 1.41-1.66 (m, 2H), 3.01-3.16 (m, 1H), 3.39-3.55 (m, 2H), 3.59-3.74 (m, 1H), 3.95-4.15 (m, 1H), 6.94 (br s, 1H), 6.95 (br s, 1H), 7.68 (dd, J=9 and 7 Hz, 1H), 8.15 (br d, J=9 Hz, 1H), 8.31 (br d, J=7 Hz, 1H).
Reaction SMILES: [NH2:1]C1C(Cl)=C(Cl)N=C(C(O)=O)C=1Cl.[Cl:14][C:15]([Cl:27])([Cl:26])[C:16]1[C:21]([Cl:22])=[C:20](Cl)[C:19]([Cl:24])=[C:18]([Cl:25])[N:17]=1.N>>[NH2:1][C:20]1[C:19]([Cl:24])=[C:18]([Cl:25])[N:17]=[C:16]([C:15]([Cl:27])([Cl:26])[Cl:14])[C:21]=1[Cl:22]
Reactant: Clc1nc(C(Cl)(Cl)Cl)c(Cl)c(Cl)c1Cl
Reactant: Nc1c(Cl)c(Cl)nc(C(=O)O)c1Cl
Agent: N
Product: Nc1c(Cl)c(Cl)nc(C(Cl)(Cl)Cl)c1Cl

Procedure:
It is known that 4-amino-3,5,6-trichloropicolinic acid is prepared by a two-step method where heptachloro-2-picoline is aminated with anhydrous liquid ammonia to form 4-amino-hexachloro-2-picoline, an intermediate product that is isolated, and which is in turn hydrolyzed with sulfuric acid to form 4-amino-3,5,6-trichloropicolinic acid. See, for example, Russian Pat. No. 445,662.
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[SH:5][C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]([CH3:25])=[CH:11][CH:12]=2)[N:7]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([S:5][C:6]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:14](=[O:24])[C:13]2[C:8](=[CH:9][C:10]([CH3:25])=[CH:11][CH:12]=2)[N:7]=1)([CH3:3])[CH3:2]
Reactant: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1-n1c(SC(C)C)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 59.4 %

Procedure:
Isopropyl bromide (0.11 mL, 1.25 mmol) was added to a suspension of 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (250 mg, 0.84 mmol) and potassium carbonate (235 mg, 1.68 mmol) in acetone (10 mL) and the mixture was heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and the any solid were filtered and washed with acetone. The filtrate was concentrated to dryness in vacuo and the crude compound was purified by column chromatography over silica gel (100-200 mesh) using 5% ethyl acetate in pet ether as eluent to afford 2-isopropylsulfanyl-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (170 mg, 59%) as semi solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[CH3:27][O:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[CH:31][C:30]=1[OH:44]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][C:30]([OH:44])=[C:29]([O:28][CH3:27])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)ccc1O

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (52 mg, 0.120 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (45 mg, 0.180 mmol) to afford the desired product (17 mg, 31%) as a yellow-green solid: 1H NMR (300 MHz, CD3OD) δ 9.19 (s, 1H), 8.36 (s, 1H), 8.10 (dd, J=8.8, 1.9 Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.30 (d, J=2.1 Hz, 1H), 7.21 (dd, J=8.2, 2.1 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 4.22 (s, 1H), 3.97 (s, 3H), 2.84 (s, 7H), 2.43 (s, 2H), 2.21 (s, 2H), 1.68 (s, 3H), 1.27-1.18 (m, 2H), 1.18-1.07 (m, 2H); ESI MS m/z 460 [C28H33N3O3+H]+; HPLC>99% (AUC), tR=10.86 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[ClH:1].[ClH:1].[N:26]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][N:12]=[C:11]([CH2:14][CH:15]4[CH2:20][CH2:19][N:18]([CH:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17][CH2:16]4)[N:10]=3)=[CH:5][CH:4]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Product: Cl
Product: c1cc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)ccc1CN1CCCCC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentylpiperidine and piperidine. HPLC: Rt=6.74 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.C1(C)C=CC=CC=1.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:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:13][CH:14]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1F
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Fc1ccccc1-c1ccc(Br)cn1
Temperature: 80 °C

Procedure:
Under nitrogen, 39.2 g (0.28 mol) of 2-fluoro-phenylboronic acid, 59.9 g (0.25 mol) of 2,5-dibromopyridine and 2.17 g of tetrakis(triphenylphosphine)palladium were dissolved in 420 ml of ethanol and 840 ml of toluene. 840 ml of a 2 N sodium carbonate solution were added, and the mixture heated to 80° C. for 1 h. Afterwards the mixture was cooled to 5 to 10° C., 800 ml of ethyl acetate were added, and the precipitated salts were separated by filtration. The organic phase of the mother liquor was separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:6]1[C:7]([OH:13])=[C:8]([CH:11]=[O:12])[CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:14])[CH3:1]
Reactant: CC1(C)CCc2cc(O)c(C=O)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCc2c1cc(C=O)c(O)c2Br
Yield: 90.8 %

Procedure:
A solution of 3.1 g (16.3 mmol) 1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde and 3.1 g (17.4 mmol) of N-bromosuccinimide in 50 ml of methylene chloride was stirred at ambient temperature for 2 days. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was filtered through silica gel (20 g) using a gradient from hexane to 2:98 (v/v) ether:hexane as eluent. There was obtained 4.0 g (14.8 mmol, 91%) of 4-bromo-1,1-dimethyl-5-hydroxyindan-6-carboxaldehyde as yellow crystals after crystallization from ethanol; mp 77.5°-78.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[S:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=[CH:41]1>>[CH3:35][C:28]1([CH3:36])[C@H:27]([C:7]2[N:6]([CH2:5][C:4]3[CH:3]=[CH:2][CH:39]=[C:38]([C:43]4[N:42]=[CH:41][S:40][CH:44]=4)[CH:37]=3)[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=2)[C@@H:29]1[C:30]([OH:32])=[O:31]
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3cscn3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C33H28N4O3S, 560.19; m/z found, 561.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.89-8.87 (m, 1H), 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.87-7.83 (m, 2H), 7.81-7.78 (m, 1H), 7.77-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.59-7.55 (m, 1H), 7.54-7.52 (m, 1H), 7.43-7.39 (m, 1H), 7.34-7.31 (m, 2H), 7.15-7.11 (m, 1H), 6.99-6.96 (m, 1H), 5.51-5.38 (m, 4H), 2.29 (d, J=8.2, 1H), 2.16 (d, J=8.2, 1H), 1.18 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:20]O>CC(OC)(C)C>[CH3:20][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:10][C:2]=1[NH2:1]
Reactant: CO
Reactant: CCCCOc1ccc(C(=O)O)c(N)c1
Solvent: COC(C)(C)C
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(C(=O)OC)c(N)c1

Procedure:
A mixture of 2-amino-4-butoxybenzoic acid (2.0 g), thionyl chloride (1.2 g) and methanol (33 mL) was boiled under reflux for 24 hours. The reaction solution was diluted with MTBE and washed with sodium hydroxide solution. The organic phase was dried and concentrated. The product with the molecular weight of 223.27 (C12H17NO3) was obtained in this way; MS (ESI): 224 (M+H+).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][C:13]2=[O:24])=[CH:9][CH:8]=1.Cl[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:26]=[CH:25][C:10]([CH2:11][N:12]2[CH:17]=[N:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][N:29]=4)[CH2:20][CH2:19]3)=[N:14][C:13]2=[O:24])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1nc(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 4.9 %

Procedure:
An N,N-dimethylformamide suspension (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9, 2-chloro-5-nitropyridine (16 mg, 0.10 mmol) and potassium carbonate (18 mg, 0.20 mmol) was stirred at 100° C. for 1 hour. After the completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed three times. The organic layer was washed with brine, was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by preparative silica gel thin-layer chromatography to obtain the title compound (2.1 mg, yield: 4.9%).
Reaction SMILES: [Li]CCCC.N(C(C)C)C(C)C.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[O:21][CH3:22].[C:23](=[O:25])=[O:24]>C1COCC1.CCOCC>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]([F:20])[C:15]=1[O:21][CH3:22]
Reactant: O=C=O
Reactant: COc1c(F)cccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(C(=O)O)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
n-BuLi (17.0 mL, 42.5 mmol) was added dropwise to the solution of NH(i-Pr)2 (4.50 g, 44.5 mmol) in 70 mL of THF at −70° C. The mixture was stirred at 0° C. for 15 minutes and then cooled to −70° C. again. The solution of 1-bromo-3-fluoro-2-methoxybenzene (8.30 g, 40.5 mmol, in 30 mL of THF) was added dropwise. The resulting mixture was stirred at −70° C. for 1 hour then poured into fresh dry ice and stirred overnight. The mixture was diluted with 1 L of ether and washed with water twice. The combined water layer was washed with ether then acidified to pH=2 with hydrochloric acid and extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-bromo-2-fluoro-3-methoxybenzoic acid.
Reaction SMILES: [I:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.[CH3:15][O-].[Na+].[C:18](=[O:20])=O>C(N(CC)C1C=CC=CC=1)C.CO>[CH3:15][O:8][C:5]1[N:4]=[C:3]([O:20][CH3:18])[C:2]([I:1])=[CH:7][N:6]=1
Reactant: O=C=O
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: COc1ncc(I)c(OC)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A dry 1L round-bottomed flask was charged with 5-iodouracil (50 g, 0.21 mol), phosphorus oxychloride (300 ml), and N,N-diethylaniline (6 drops). The heterogenous mixture was heated in a 120° C. oil bath under a nitrogen atmosphere for 24 hours. The phosphorus oxychloride was distilled off (some product co-distills off). The reaction solution was next slowly and cautiously poured over ice (1L) and solid sodium bicarbonate keeping the internal temperature at or below −20° C. (This was accomplished by cooling in a dry-ice acetone bath). Once the addition was complete, the reaction mixture was adjusted to pH 7 by addition of solid sodium bicarbonate. The mixture was extracted with methylene chloride and the organic fractions dried by passage through phase separator paper. The crude solution of 2,4-dichloro-5-iodopyrimidine was immediately added dropwise to a solution containing MeOH (400 ml) and sodium methoxide (28.8 g, 0.533 mol). This addition took 1 hour. The reaction was then stirred at room temperature overnight. The solution was neutralized with CO2 (gas), extracted with methylene chloride, dried over anhydrous Na2SO4 filtered and concentrated. The crude product was adsorbed onto silica gel (100 g) and loaded onto a 400 g silica gel flash chromatography column. The column was eluted with 90:10 hexanes: ethyl acetate (v:v). The appropriate fractions were combined and concentrated to a white solid as the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2)([O-])=O.[H][H]>CO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[CH:7]2
Reactant: O=c1ccc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: Nc1ccc2[nH]c(=O)ccc2c1

Procedure:
In a Parr catalytic hydrogenation apparatus 6-nitrocarbostyril, 5.3 g (0.028 mole), in 150 mL of methanol and 0.5 g PtO2 were shaken in a hydrogen atmosphere. The resulting yellow solid was extracted with refluxing methanol and the extract evaporated to yield 6-aminocarbostyril, 3.5 g, as yellow crystals; m.p. 315°-317° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5](CN)=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([N:18]=[C:19]=[O:20])[CH:15]=[CH:16][CH:17]=1)#[N:11].Cl.C(OCC)(=O)C.C[N:29]([CH3:32])C=O>>[C:10]([C:12]1[CH:13]=[C:14]([NH:18][C:19]([NH:29][C:32]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=2[CH3:5])=[O:20])[CH:15]=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: NCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1NC(=O)Nc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromobenzyl amine (3.81 g, 20 mmol) and 3-cyanophenyl isocyanate (2.65 g, 18.4 mmol) in dimethylformamide (60 mL) was stirred at ambient temperature for 48 h. The reaction was partioned between 1N hydrochloric acid solution (200 mL) and ethyl acetate (200 mL). The ethyl acetate solution was washed with water (5×100 mL), then dried (MgSO4) and evaporated to give 5.33 g of N-(3-cyanophenyl)-N'-(methyl(4-bromo)phenyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCl>[CH2:19]([O:18][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
20 g of 4-aminophenol (Mw=109.13; 0.18324 mol) are suspended in 200 cm3 of anhydrous dichloromethane, under an inert atmosphere. The suspension is cooled to a temperature of 0° C. in a bath of ice and 16.4 cm3 of anhydrous pyridine (Mw=79.10; d=0.981; 0.2034 mol) are then added. 17.6 cm3 of ethyl chloroformate (Mw=108.53; d=1.13; 0.18324 mol) are then added dropwise so as to keep the mixture at a temperature below 10° C. The reaction mixture is kept stirring for two hours. The mixture is poured onto one litre of ice-cold water and then extracted with ethyl acetate. The organic phase is washed with water and then dried, filtered and evaporated under vacuum. After recrystallization from a heptane/ethyl acetate mixture, 21 g of a white powder are obtained, which corresponds to a yield of 63%. The melting point of the product obtained is 127.2° C. The 1H NMR spectrum and the elemental analysis are in accordance with the expected product.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]#N)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1([Mg]Br)[CH2:30][CH2:29]1.Cl.C1C[O:37]CC1>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:37])[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Reactant: CC(C)(C)[Si](OCc1cc(C#N)ncn1)(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)(C)[Si](OCc1cc(C(=O)C2CC2)ncn1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, to a solution of 6-(((tert-butyldiphenylsilyl)oxy)methyl)pyrimidine-4-carbonitrile (11.3 g) in THF (100 mL) was added 0.70 M cyclopropylmagnesium bromide (86 mL) at 0° C., and the mixture was directly stirred for 30 min. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a brown oil. This compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.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>[NH2:32][C:33]1[CH:34]=[C:35]([C:25]2[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:29])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])=[N:21][C:22]([S:27][CH3:28])=[N:23][CH:24]=2)[CH:36]=[CH:37][C:38]=1[F:39]
Reactant: Nc1cc(B(O)O)ccc1F
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ncc(-c2ccc(F)c(N)c2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of the Intermediate 45 (2.0 g, 3.77 mmol), 3-amino-4-fluoro phenylboronic acid (0.92 g, 5.94 mmol), Na2CO3 (0.88 g, 8.3 mmol) and catalytic amount of Pd(PPh3)4 in a mixture of toluene/EtOH/water (4:2:1) (28 mL) was stirred at 80° C. for 1 h. The mixture was cooled, and the solvents were removed. Water (5 mL) was added and the mixture was extracted with dichloromethane (3×5 mL). The combined organic fractions were washed with brine (5 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/isohexane to give the title compound as a yellow gum. 1H NMR (CDCl3, 500 MHz) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.77 (s, 2H), 7.10 (dd, J=11, 8 Hz, 1H), 6.77 (dd, J=8.5, 2.5 Hz, 1H), 6.64 (m, 1H), 5.72 (d, J=8.5 Hz, 1H), 4.98 (d, J=17.5 Hz, 1H), 4.40 (m, 1H), 4.10 (d, J=17.5 Hz, 1H), 2.64 (s, 3H), 0.74 (d, J=6.5 Hz, 3H). LCMS=561.5 (M+H)+.
Reaction SMILES: [CH2:1]([CH:15]1[CH2:20][C:19](=O)[O:18][C:16]1=[S:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CCC.[OH-:22].[Na+:23].[OH2:24]>CO>[CH2:19]([O:18][C:16](=[S:17])[CH2:2][CH2:1][C:15]([O-:24])=[O:22])[CH2:20][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Na+:23].[Na+:23].[CH2:19]([O:18][C:16](=[S:17])[CH2:3][CH2:4][C:5]([O-:24])=[O:22])[CH2:20][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O
Reactant: CCCCCCCCCCCCCCC1CC(=O)OC1=S
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCOC(=S)CCC(=O)[O-]
Reaction time: 1 h

Procedure:
12.2 g n-tetradecylthiosuccinic anhydride prepared according to the method of Zienty et al. [J. Org. Chem. 27, 3144 (1962)] was dissolved in methanol. Then, 3.6 g of sodium hydroxide in 15 ml of water was added and the mixture stirred for one hour. The crystalline precipitate was filtered off, dissolved in 150 ml of hot water and decolorized with charcoal. The filtrate from the charcoal treatment was then concentrated in vacuo and poured into acetone to precipitate the disodium n-tetradecylthiosuccinate. After drying the product in a vacuum oven, the yield was 13.2 g (0.24% moisture). The structure of the product was confirmed by NMR analysis.