Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([CH3:27])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:22][CH3:23])CC)=[O:18].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46]C(C#N)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:23]([C:22]3[NH:19][C:17](=[O:18])[C:16]4[C:15]([CH:27]=3)=[C:14]([Br:13])[CH:26]=[CH:25][CH:24]=4)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C#N)cc2)CC1
Reactant: CCN(CC)C(=O)c1cccc(Br)c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4c(Br)cccc4c(=O)[nH]3)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a stirred solution of N,N-diisopropylamine (1.56 mL, 11.10 mmol) in THF (5 mL) under N2 at −78° C. was added n-BuLi (2.5M in hexanes) (4.44 mL, 11.10 mmol) and the reaction stirred at −78° C. for 20 min, after which time a solution of 3-bromo-N,N-diethyl-2-methyl-benzamide (1 g, 3.70 mmol) in THF (5 mL) was added, and the reaction stirred at −78° C. for 30 minutes. A solution of 4-(4-cyano-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 3.70 mmol) in THF (5 mL) was added and the reaction stirred at −78° C. for 2 h. The reaction was quenched with ice and water, EtOAc added and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 100% EtOAc to afford 4-[4-(5-bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester as a cream solid (1.22 g, 66%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[O:36]=[C:37]1[CH2:41][CH2:40][C:39](=[O:42])[N:38]1[CH:43](CC([O-])=O)[C:44]([O-:46])=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37](=[O:36])[CH2:41][CH2:40][C:39]([NH:38][CH2:43][CH2:44][O:46][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:42])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C([O-])CC(C(=O)[O-])N1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 0.32 h

Procedure:
Compound 181 was prepared from compound 28 and (2,5-dioxopyrrolidin-1-yl)succinate following the procedure outlined in example 175. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, CH3CN/H2O/CF3COOH=0.05/100/0.05 increasing to CH3CN/H2O/CF3COOH=90/100/0.05 within 19 min; Detector, UV 254 nm. This resulted in 201 mg (78%) of a TFA salt of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide as a white solid. 1H-NMR (300 MHz, DMSO+DCl, ppm): δ 7.76 (d, J=7.5 Hz, 2H), 7.68 (s, 2H), 7.63˜7.52 (m, 6H), 6.64 (s, 1H), 4.88˜4.82 (m, 2H), 4.62˜4.42 (m, 4H), 3.76˜3.60 (m, 4H), 3.43˜3.30 (m, 25H), 3.14˜3.10 (m, 4H), 2.97 (s, 6H), 2.86˜2.82 (m, 4H), 2.27 (s, 4H). MS (m/z): 589 [M/2+1]+.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15]CC(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34][C:35](=[O:45])[CH:36](SC1SC(N)=NC=1)[CH3:37])C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([O:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:37][CH2:36][C:35]([OH:45])=[O:34])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: CC(C)CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Product: CC(C)CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared as described for the synthesis of {2-[3-cyclohexyl-3-(trans-4-isobutoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-acetic acid ethyl ester in the coupling step.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[CH2:13]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([N:31]=[N+:32]=[N-:33])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:31]([CH2:13]/[CH:12]=[CH:11]/[CH:10]=[CH:9]/[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OC/C=C/C=C/CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC/C=C/C=C/CCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2E,4E)-7-Phenylhepta-2,4-dien-1-ol (6.8 g) was dissolved in dry toluene (130 ml) and cooled in an ice-salt bath. Diphenyl phosphorazidate (7.83 ml) was added, followed by dropwise addition of DBU (6.53 ml) in dry toluene (15 ml). The mixture was stirred for 15 h while warming to room temperature. Solvents were evaporated and the residue was partitioned between diethyl ether and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography yielded a colorless liquid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([O:42]CC)=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([OH:42])=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OCC)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)O)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 69) (16.47 g, 0.0274 moles) in methanol (164 ml) was added aqueous sodium hydroxide (30.2 ml of a 1 M solution, 0.0302 moles) and the resultant mixture was stirred at ambient temperature under an atmosphere of nitrogen for 1.5 hours. The reaction mixture was then concentrated in vacuo and to the residue was added dichloromethane (160 ml) and deionised water (160 ml). The pH of this mixture was adjusted to pH 4 by the addition of aqueous 2M hydrochloric acid with stirring. The organic phase was separated and the aqueous layer was extracted with dichloromethane (75 ml). The organic phases were then combined, dried over anhydrous magnesium sulphate and concentrated in vacuo to give the title compound (15.5 g) as a cream coloured foam that was used as such for the next step. If necessary, this crude product can be purified by standard means, such as flash chromatography on silica gel.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
7.00 g (30.6 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.7 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenyl-phosphine)palladium(II) chloride and 40.7 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelute, washed with dichloromethane and the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH2:34]([N:36]([CH2:42][CH3:43])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:39]2[CH2:40][CH2:41][CH:37]([N:36]([CH2:42][CH3:43])[CH2:34][CH3:35])[CH2:38]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: CCN(CC)C1CCNC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCN(CC)C1CCN(C(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)C1

Procedure:
5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (95 mg, 0.19 mmol) was coupled with diethyl-pyrrolidin-3-yl-amine (50.6 mg, 0.25 mmol) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) at rt for 3 days to give the titled compound.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[K+].[NH:12]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:13]([C:15]([NH:17][C@H:18]([C:22]([N:24]1[CH2:32][CH2:31][CH2:30][C@H:25]1[C:26]([CH2:28]Br)=[O:27])=[O:23])[CH:19]([CH3:21])[CH3:20])=[O:16])[CH3:14]>>[NH:12]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C@H:13]([C:15]([NH:17][C@H:18]([C:22]([N:24]1[CH2:32][CH2:31][CH2:30][C@H:25]1[C:26]([CH2:28][O:8][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:9])=[O:27])=[O:23])[CH:19]([CH3:20])[CH3:21])=[O:16])[CH3:14]
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)CBr
Agent: [F-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)COC(=O)c1ccccc1

Procedure:
Benzoic acid (0.275 g, 2.25 mmol), KF (0.131 mg, 2.25 mmol), 13 (0.56 g, 1.13 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2cc[nH]c2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 27 %

Procedure:
The title compound is prepared from 1H-indole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 27% of theory; LC (method 4): tR=2.01 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:21]=2[S:20](=[O:30])(=[O:29])[N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][N:39]=1>CS(C)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([O:28][C:38]3[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][CH:41]=[CH:40][N:39]=3)=[CH:27][C:21]=2[S:20](=[O:29])(=[O:30])[N:19]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: O=[N+]([O-])c1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3cc(Oc4ncccc4[N+](=O)[O-])ccc3N2)c(O)c2ccccc21
Temperature: 110 °C
Yield: 78.1 %

Procedure:
A mixture the product of Example 321C (10.0 mg, 0.02 mmol), cesium carbonate (27.7 mg, 0.09 mmol), and 2-bromo-3-nitropyridine (8.4 mg, 0.04 mmol) in dimethylsulfoxide (0.3 mL) was stirred while heating at 110° C. in a microwave reactor for 20 minutes. After cooling to 25° C., the mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a 0-100% dichloromethane in hexane step gradient to give the title compound as a yellow solid (8.6 mg, 68%). MS (ESI−) m/z 549 (M−H)−. 1H NMR (300 MHz, CDCl3) δ 1.13 (d, J=6.62 Hz, 6 H) 2.00 (m, 1 H) 2.81 (m, 2 H) 5.73 (m, 1 H) 7.23 (m, 1 H) 7.40 (m, 2 H) 7.50 (dd, J=8.82, 2.57 Hz, 1 H) 7.82 (m, 2 H) 7.97 (m, 1 H) 8.27 (dd, J=8.09, 1.10 Hz, 1 H) 8.35 (dd, J=4.78, 1.84 Hz, 1 H) 8.42 (dd, J=8.09, 1.84 Hz, 1 H) 14.39 (s, 1 H) 15.02 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: BrCCCN1C=CC=CC1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.: 145-147° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyridine hydrobromide is as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:4](C(O)=O)[C:3]=1[C:14]([OH:16])=[O:15].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(F)c1F
Temperature: 30 °C
Reaction time: 21 h

Procedure:
In an autoclave having an inner volume of 1 liter, 150 g (0.630 mole) of 3,4,5,6-tetrafluorophthalic acid containing no sulfate ion, 29.1 g (0.220 mole) of ammonium sulfate, and 500 g of water were placed and heated and stirred for reaction at 160° C. for 21 hours [pH 1.74 at 30° C. at the time of charging]. After completion of the reaction, the reaction suspension was cooled to room temperature, filtered, washed with water, and then dried, to produce 2,3,4,5-tetrafluorobenzoic acid. Calculation from the amount obtained by filtration and the amount obtained by extraction as in Example 1 reveals that this example produced 2,3,4,5-tetrafluorobenzoic acid in a yield of 85.8 mole %.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]([CH:21]2[C:29]3[C:24](=[C:25]([C:30]4[C:35]([CH3:36])=[CH:34][C:33]([OH:37])=[CH:32][C:31]=4[CH3:38])[CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].[CH2:46]([S:48][CH2:49][CH2:50]O)[CH3:47].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OC(C)C)(C)C>[CH2:46]([S:48][CH2:49][CH2:50][O:37][C:33]1[CH:34]=[C:35]([CH3:36])[C:30]([C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:24]=2[CH2:23][CH2:22][CH:21]3[N:8]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])(=[O:10])=[O:11])[C:6]2[CH:5]=[CH:4][C:3]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:2]([F:1])[CH:7]=2)=[C:31]([CH3:38])[CH:32]=1)[CH3:47]
Reactant: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(O)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: CCSCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(C2CCc3c(-c4c(C)cc(OCCSCC)cc4C)cccc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 93.1 %

Procedure:
To a solution of ethyl 3-(2-fluoro-4-{[4-(4-hydroxy-2,6-dimethylphenyl)-2,3-dihydro-1H-inden-1-yl][(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.00 g, 1.58 mmol), 2-(ethylthio)ethanol (0.219 mg, 2.06 mmol) and tributylphosphine (0.417 mg, 2.06 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.520 g, 2.06 mmol) under stirring at room temperature, and the mixture was stirred for 16 hr. The reaction mixture was diluted with diisopropyl ether, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (1.06 g, yield 93%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[CH:42][C:41]=1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57].C(=O)([O-])[O-].[Na+].[Na+]>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>[OH:39][C:40]1[C:45]([C:2]2[C:10]3[C:9]([NH:11][CH:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)=[CH:44][CH:43]=[CH:42][C:41]=1[NH:55][S:56]([CH3:59])(=[O:58])=[O:57]
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2O)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc(C(C)Nc3ncnc4c3c(-c3cccc(NS(C)(=O)=O)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 17.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (61 mg, 0.10 mmol) was treated with N-(2-hydroxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (200 mg, 0.26 mmol, prepared from N-(3-bromo-2-hydroxyphenyl)-methanesulfonamide and bis(pinacolato)diboron according to Preparation 19b), sodium carbonate (27 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (25 mg, 0.03 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 12 mg (15% yield) of the title compound. Purity 90%.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.Cl[CH2:14][C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:12]=[C:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH:3]=[C:2]1[O:1][CH2:14][C:15]#[N:16]
Reactant: N#CCCl
Reactant: O=c1c(O)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1coc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 77.9 %

Procedure:
A mixture of 3-hydroxychromone (4.86 g, 0.03 mole), chloroacetonitrile (2.26 g, 0.03 mole) and potassium carbonate (3.0 g, 0.02 mole) in dimethylformamide (40 ml) is stirred at 100° C. under nitrogen for 4 hrs. The reaction mixture is cooled, poured into water (200 ml), filtered, washed with water and sucked dry. Recrystallization from methanol gives white crystals (4.7 g, 94%), mp 145°-146° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[C:22](Cl)=[N:23][C:24]([Cl:27])=[N:25][CH:26]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][CH:10]([O:12][C:22]2[C:21]([Br:20])=[CH:26][N:25]=[C:24]([Cl:27])[N:23]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CC(O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CC(Oc2nc(Cl)ncc2Br)C1
Yield: 94.7 %

Procedure:
To a solution of (3-hydroxy-cyclobutyl)-carbamic acid tert-butyl ester (2.5 g, 13.3 mmol) in THF (40 mL) were added Cs2CO3 (8.6 g, 26.6 mmol) and 5-bromo-2,4-dichloro-pyrimidine (3 g, 13.3 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was filtered and concentrated, diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (3×100 mL) and the combined organic extracts were washed with brine (60 mL), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel to give the product (4.75 g, 12.6 mmol, yield: 95%). ESI-MS (M+1): 378 calc. for C13H17BrClN3O3 377.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Nc2ccccc2)c2ccccc2c1O

Procedure:
A mixture of 1-bromo-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (810 mg, 2.5 mmol, Example D-28 a) and aniline (3 ml) was stirred in a pressure tube in a microwave oven at 150° C. for 20 min. The reaction was repeated on the same scale. Both reaction mixtures were combined, EtOAc (100 ml) was added and the mixture was washed with H2O (5×30 ml, pH=1-2). The organic phase was dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using hexanes/EtOAc as the eluent to give 770 mg of 4-hydroxy-1-phenylamino-isoquinoline-3-carboxylic acid butyl ester; MS-(+)-ion: M+1=337.21.