Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:30][C:31]1[N:40]=[C:39]([NH2:41])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=2)[N:32]=1>O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:42]([C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([NH2:30])[N:40]=[C:39]3[NH2:41])(=[O:43])=[O:44])[C:4]1=[O:17])#[N:13]
Reactant: Nc1nc(N)c2cc(S(=O)(=O)Cl)ccc2n1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4nc(N)nc(N)c4c3)C2=O)c1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.50 g, 2 mmol) in 8 mL of H2O is added triethyl amine (0.7 g, 7 mmol). After stirring for 10 minutes, 2,4-diamino-quinazoline-6-sulfonyl chloride sulfate salt (0.71 g, 2 mmol) is added. The solution is refluxed for 1 hour. After this time, the solution is cooled to ambient temperatures. The solution is filtered. The collected solid is dried under vacuum to give the title compound (0.22 g, 0.5 mmol) as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7](Br)=[CH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1.[CH:24](=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1>[OH:36][CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:7]#[C:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[O:14][CH:15]=1
Reactant: CC[Si](CC)(CC)c1cc(CCC=C(Br)Br)co1
Reactant: CCCCCCCCCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(O)C#CCCc1coc([Si](CC)(CC)CC)c1
Reaction time: 2 h

Procedure:
n-Butyl lithium (a 2.5M solution in tetrahydrofuran; 0.42 ml, 1.04 mmol) was added dropwise to a solution of 4-(4,4-dibromo-3-butenyl)-2-triethylsilylfuran (200 mg, 0.51 mmol) in tetrahydrofuran (8 ml) at -78° under argon. After 2 hours, a solution of 1-dodecanal (102 mg, 0.56 mmol) in tetrahydrofuran (1 ml) was added. Stirring was continued for 14 hours, while the cooling bath attained room temperature. The mixture was quenched with water and was extracted with ethyl ether. Evaporation of the dried (magnesium sulfate) extracts gave a residue, which was purified by a silica column with 15% ethyl ether/hexane to give the titled alcohol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:25][C:24]3[CH:26]=[C:20]([O:19][CH3:18])[CH:21]=[CH:22][C:23]=3[CH3:27])=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Reactant: COc1ccc(C)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(C)c(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Temperature: 115 °C
Yield: 62.1 %

Procedure:
A mixture of 0.9 g (3.36 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 0.55 g (4.0 mmol) of 5-methoxy-2-methylaniline, 0.46 g (4.0 mmol) of pyridine hydrochloride in 10.0 mL of 2-ethoxyethanol is heated at 115° C. for 1 hour, cooled and poured into a saturated solution of sodium bicarbonate. The oil is extracted with methylene chloride, dried over anhydrous sodium sulfate and the solvent is evaporated to yield a foam. This is purified by silica gel chromatography, eluting with methylene chloride/methanol (99.5:0.5) to yield 0.77 g of 7-chloro-4-(5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile as a yellow solid, mp 180–182° C.
Reaction SMILES: [CH2:1](C1C=C2C(COC2=O)=CC=1)[CH3:2].Br[C:14]1[C:15]([O:33][CH3:34])=[C:16]([C:22]([CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(B(CC)CC)C>>[C:27]1([S:26][CH2:25][C:22]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:33][CH3:34])[C:14]([CH2:1][CH3:2])=[CH:24][CH:23]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCc1ccc2c(c1)C(=O)OC2
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Agent: CCB(CC)CC
Product: CCOC(=O)c1c(CSc2ccccc2)ccc(CC)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 18, starting from ethyl 3-bromo-6-(phenylthiomethyl)-2-methoxybenzoate (Intermediate 73) and triethyl borane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[N:8]/[CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:3][CH:2]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([N+:40]#[C-:41])S(C2C=CC(C)=CC=2)(=O)=O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].COC(C)(C)C>CN(C=O)C>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:40]=[CH:41][N:8]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(/N=C/c2ccncn2)CC1
Reactant: [C-]#[N+]C(c1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl 4-{[(1E)-pyrimidin-4-ylmethylene]amino}piperidine-1-carboxylate (C13) (57.66 g, 198.6 mmol), 1-fluoro-4-{isocyano[(4-methylphenyl)sulfonyl]methyl}benzene (C2) (38.30 g, 132.4 mmol) and potassium carbonate (36.59 g, 264.8 mmol) in DMF (575 mL) was stirred for 18 hours. The reaction was filtered, and the solids were washed with ethyl acetate and discarded. The combined filtrates were diluted with ethyl acetate (1 L) and washed with water (2×1 L), and the combined aqueous layers were extracted with ethyl acetate (500 mL). Concentration of the combined organic layers in vacuo provided a solid, which was heated at reflux with tert-butyl methyl ether (400 mL), then cooled to room temperature and granulated for 1 hour. The solid was collected by filtration and washed with additional tert-butyl methyl ether; this filtrate was concentrated under reduced pressure and treated in the same way, using 75 mL of tert-butyl methyl ether, to obtain a second crop. The combined solids provided the product as a white solid. Yield: 41.70 g, 98.47 mmol, 74%. 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 1.81-1.92 (m, 2H), 2.16 (br d, J=12 Hz, 2H), 2.77-2.85 (m, 2H), 4.30 (br s, 2H), 4.90 (tt, J=12.0, 3.8 Hz, 1H), 7.04 (dd, J=8.7, 8.7 Hz, 2H), 7.17 (dd, J=5.3, 1.4 Hz, 1H), 7.41 (dd, J=8.9, 5.4 Hz, 2H), 7.79 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 9.29 (d, J=1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:28])[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:42]([O:41][C:39](=[O:40])[C:31]1[CH:32]=[C:33]([O:26][C:23]2[CH:24]=[CH:25][C:20]([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:28])[CH2:9][C:10]([C:12]3[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=3)=[O:11])=[CH:21][C:22]=2[F:27])[CH:34]=[CH:35][C:30]=1[Cl:29])[CH3:43]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1Cl
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(Oc2ccc(C(CC(=O)c3ccc(=O)n(C)c3)c3ccc(Cl)cc3C)cc2F)ccc1Cl

Procedure:
In analogy to example 222, step 1, 5-[3-(4-chloro-2-methyl-phenyl)-3-(3-fluoro-4-hydroxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one (example 324, step 1) was reacted with 4-chloro-3-ethoxycarbonylphenylboronic acid in dichloromethane in the presence of copper(II) acetate, pyridine and air to give the title compound as a colourless solid, MS (ESI+): m/z=582.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:15]=[C:16]([S:19][CH2:20][C:21]([OH:23])=O)[NH:17][CH:18]=2)[CH:9]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:24]1([C:21](=[O:23])[CH2:20][S:19][C:16]2[NH:17][CH:18]=[C:14]([C:10]3[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=3)[N:15]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)CSc1nc(-c2cccnc2)c[nH]1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CSc1nc(-c2cccnc2)c[nH]1)N1CCCCC1

Procedure:
32 mg (0.069 mmol) of (4-(pyridin-3-yl)-1H-imidazol-2-ylsulfanyl)-acetic acid trifluoroacetic acid salt from step (b), 8.8 mg (0.1 mmol) of piperidine, 24.9 mg (0.076 mmol) TOTU and 15.9 mg (0.138 mmol) NEM in 4 ml of DMF were stirred at room temperature for 4 h. After evaporation, water and dichloromethane were added, the organic phase was separated, washed with water, dried, evaporated, and the product was purified by RP18 chromatography. Yield: 7 mg.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.N1C=CC=CC=1.C(OC(O)C)C.C(=O)(O)[O-].[Na+]>>[NH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(N)c3)c2cc1OC

Procedure:
A stirred mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile (3.73 g, 15 mmol), 1,3-diaminobenzene (4.86 g, 45 mmol), pyridine (1.21 ml, 15 mmol), and 45 ml of ethoxyethanol was refluxed for 30 m, cooled, and stirred with aqueous sodium bicarbonate. The resulting solid was filtered, washed with water, and dried. Recrystallization from ethanol gave a brown solid, mp 222-228° C.
Reaction SMILES: [Cl:1][CH:2]([SiH:4]([CH2:6][CH2:7]Cl)[CH3:5])[CH3:3].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[Cl:1][CH:2]([SiH:4]([CH2:6][CH2:7][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5])[CH3:3]
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(Cl)[SiH](C)CCCl
Solvent: CCOCC
Product: CC(Cl)[SiH](C)CCCc1ccccc1

Procedure:
To a solution of (α-chloroethyl)chloroethylmethylsilane (0.171 g, 1 mmol) in diethyl ether (5 ml) was added a solution of benzylmagnesium bromide (1 mmol, 1 eq). The mixture was refluxed for 12 hours, then filtered. The product was purified by distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=1>>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][CH:14]=2)=[O:19])[CH:7]=[CH:8][N:9]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1cccc2ccncc12
Product: O=C(Nc1cccc2ccncc12)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 8-aminoisoquinoline (D95) (85 mg, 0.59 mmol) and 4-biphenylcarboxylic acid (177 mg, 0.89 mmol) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.48 (s, 1H), 8.61 (d, 1H), 8.42 (br.s, 1H), 8.22 (d, 1H), 8.10 (d, 2H), 7.79 (d, 2H), 7.68-7.76 (m, 5H), 7.51 (t, 2H), 7.43 (t, 1H).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([CH:18]3[CH:23](Cl)[CH2:22][CH2:21][CH2:20][C:19]3=[O:25])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1)[CH3:3].[C:29]1([SH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClC1C2CCS(=O)(=O)C=2C=CC=1C(C1C(Cl)CCCC1=O)=O.C(S)C>>[CH3:1][CH:2]([O:4][CH:5]1[C:14]2[C:9](=[C:10]([CH3:26])[CH:11]=[C:12]([C:16]([CH:18]3[CH:23]([S:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21][CH2:20][C:19]3=[O:25])=[O:17])[C:13]=2[CH3:15])[S:8](=[O:28])(=[O:27])[CH2:7][CH2:6]1)[CH3:3]
Reactant: Cc1cc(C(=O)C2C(=O)CCCC2Cl)c(C)c2c1S(=O)(=O)CCC2OC(C)C
Reactant: Sc1ccccc1
Agent: O=C1CCCC(Cl)C1C(=O)c1ccc2c(c1Cl)CCS2(=O)=O
Solvent: CCS
Product: Cc1cc(C(=O)C2C(=O)CCCC2Sc2ccccc2)c(C)c2c1S(=O)(=O)CCC2OC(C)C

Procedure:
The target compound was prepared in the same manner as described in Example II-2 except that 4-(2-propyl)oxy-5,8-dimethyl-6-(3-chloro-1-oxocyclohexan-2-yl)carbonylthiochroman-1,1-dioxide and benzenethiol were used instead of 4-chloro-5-(3-chloro-1-oxocyclohexan-2-yl)carbonyl-2,3-dihydrobenzothiophene-1,1-dioxide and ethanethiol, respectively.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)([O-:8])=[O:7].N1C=CC=CC=1>O1CCCC1>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CCC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Propionyl chloride (25.0 g, 270 mmol) was added dropwise to a solution of 4-nitroaniline (24.9 g, 180 mmol) and pyridine (43.7 ml, 540 mmol) in tetrahydrofuran (500 ml) under ice-cooling, the mixture was stirred under ice-cooling for 2 hour, and the solvent was distilled off under reduced pressure. The residue was poured into ice-water, and 33.5 g (95.7%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O.O>[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 28.91 g of 3-fluoro-4-morpholinyl-aniline and 27.88 g of sodium bicarbonate in 500 mL of acetone and 250 mL of water at 0° C. was added 28.68 g of benzyl chloroformate. After stirring the mixture for 1.5 hours, the mixture was poured onto 1000 cc of ice and water, and the ice allowed to melt. The precipitated solid was collected by filtration and washed with 3×250 ml of water, and then dried in a vacuum oven at 75° C. to give a gray-purple solid. This was recrystallized from acetone-water to give a cream-colored solid, mp=123°-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12](=O)([O-])[O-].[K+].[K+].CO>CC(C)=O>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cccc2c1CCC2=O
Reaction time: 10 h
Yield: 79.4 %

Procedure:
To a mixture of 4-hydroxy-indan-1-one (14.5 g, 0.0979 mol) and 27.08 g (0.195 mol) of potassium carbonate was added 500 ml of acetone and 48.7 ml (0.78 mol) of methanol with stirring and the resulting mixture was heated to reflux for 4 h, cooled, and allowed to stand at room temperature for 10 h. The above mixture was filtered concentrated under vacuo, the solid residue was dissolved in methanol, heated and filtered. The filtrate was concentrated to a volume of 100 ml, cooled and filtered to afford 12.6 g (79%) of 4-methoxy-indan-1-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:27])=[O:26]
Reactant: CCCCCCCC(=O)NCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCCOS(C)(=O)=O
Yield: 81.6 %

Procedure:
To a solution of 2.00 g (7.77 mmol) of N-(5-hydroxypentyl)caprylamide and 1.30 ml (9.32 mmol) of triethylamine in 50 ml of methylene chloride was added 0.72 ml (9.32 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 1.95 g of the desired compound (74.8%, colorless powder), mp: 67.0-68.0° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2Br)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:26]([N:28]([CH2:45][CH3:46])[CH2:29]/[CH:30]=[CH:31]\[Sn](CCCC)(CCCC)CCCC)[CH3:27].[F-].[Cs+]>C1COCC1>[Br:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:31]=[CH:30]\[CH2:29][N:28]([CH2:45][CH3:46])[CH2:26][CH3:27])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2Br)ccc(Br)c1OC
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Yield: 62.6 %

Procedure:
A mixture of methyl 3-bromo-6-(2-bromo-4-fluorobenzenesulfonylmethyl)-2-methoxybenzoate (Intermediate 70, 5.85 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 5.00 g) and cesium fluoride (3.29 g) in THF (100 mL) was de-gassed and purged with nitrogen for 5 minutes. Palladium tetrakis-(triphenylphosphine) (0.720 g) was added and the reaction mixture was heated at reflux overnight. The mixture was cooled, diluted with ethyl acetate, filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10% to give methyl 3-bromo-6-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylmethyl]-2-methoxybenzoate (3.9 g) as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[NH2:13]>O>[F:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:12]=1[N:13]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: Nc1c(F)cccc1F
Solvent: O
Product: Cc1cc(O)cc(=O)n1-c1c(F)cccc1F
Temperature: 170 °C
Yield: 37.5 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170° C. under argon atmosphere for 20 min. The water formed was removed using a Dean-stark apparatus. The melt was cooled, the dark solid was tritutrated with EtOAc., and filtered. This material was washed thoroughly with EtOAc to afford the desired product 1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one 6.5 g (35%) as a light brown solid: 1H NMR (CD3OD/400 MHz) δ7.56 (m, 1H), 7.19 (m, 2H), 6.09 (m, 1H), 5.77 (d, 1H, J=2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z 238.0679 (M+H C12H10NO2F2 requires 238.0674).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: IC1CCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCCC3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (12 g, 57.9 mmol) (Acros Organics), powdered potassium carbonate (5.4 g, 39 mmol), iodocyclopentane(7 mL, 60.8 mmol) (Aldrich) and a catalytic amount of 18-crown-6 in acetonitrile (90 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated to a yellow solid and dried under vacuum to give 1-cyclopentyl-4-(4-nitrophenyl)piperazine) (6.6 g, 41%.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:10]=[C:11]([C:22]3([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23]3)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[N:6][C:7]=1[OH:8].[CH2:29]([O:31][CH2:32][C@@H:33]([N:35]=[C:36]=S)[CH3:34])[CH3:30].C(N=C=NC(C)C)(C)C>C(O)C>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]1[NH:12][C:11]([C:22]2([C:25]([O:27][CH3:28])=[O:26])[CH2:24][CH2:23]2)=[N:10][C:9]=1[C:5]1[N:6]=[C:7]2[O:8][C:36]([NH:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH2:29][CH3:30])=[N:1][C:2]2=[CH:3][CH:4]=1
Reactant: CCOC[C@H](C)N=C=S
Reactant: COC(=O)C1(c2nc(-c3ccc(N)c(O)n3)c(-c3ccc(F)cc3F)[nH]2)CC1
Agent: CC(C)N=C=NC(C)C
Solvent: CCO
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(C(=O)OC)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 85 °C
Reaction time: 16 h
Yield: 22.9 %

Procedure:
A mixture of methyl 1-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]cyclopropanecarboxylate (4 g, 10.35 mmol) and (2S)-1-ethoxy-2-isothiocyanato-propane (2.379 g, 15.53 mmol) are dissolved in ethanol (34 mL). The mixture is heated to 85° C. in a sealed flask for 16 h. Diisopropyl carbodiimide (3.21 g, 20.71 mmol) is added dropwise and the mixture is stirred at 85° C. for 16 h, after which time an additional 3 g of diisopropyl carbodiimide is added and the mixture is heated at 85° C. for an additional 4 h. The solvent is evaporated and the residue is purified by normal phase chromatography (120 g silica-gel cartridge, using a hexane-ethanol gradient to afford the title compound (1.180 g, 24%). LC-ES/MS m/z 498.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]1)#[CH:20].F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:18][N:16]1[CH:17]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:20]#[C:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:14]=[N:15]1
Reactant: Cn1cc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Reactant: C#Cc1ccccc1C1(C(N)=O)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C3(C(N)=O)CC3)n2)cn1
Temperature: 100 °C

Procedure:
To a degassed mixture of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine A74 (0.178 g, 0.640 mmol), 1-(2-ethynylphenyl)cyclopropanecarboxamide K6 (0.172 g, 0.928 mmol), PdCl2(PPh3)2 (0.005 g, 0.007 mmol), t-Bu3PH.BF4 (0.005 g, 0.02 mmol) and copper(I) iodide (0.003 g, 0.02 mmol) in DMF (8.0 mL) was added DIPEA (0.33 mL, 1.9 mmol). The mixture was heated in the microwave for 2×20 minutes at 100° C. before being concentrated under reduced pressure. Purification by silica gel column chromatography (Isolera, 0-100% EtOAc petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) gave the title compound A75 (0.120 g, 44%). LCMS-D: rt 3.30 min; m/z 427.2 [M+H]+.