Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:7]=1[O:14]C)=[O:4].B(Br)(Br)Br.O>ClCCl>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[OH:14])=[O:4]
Reactant: COc1ccc(OC)c(NC(=O)CCl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)Nc1cc(O)ccc1O
Reaction time: 8 h

Procedure:
Compound 46 (5 g, 21.7 mmol) was dissolved in dichloromethane followed by the dropwise addition of boron tribromide (1M solution in dichloromethane, 84 ml, 84 mmol) at 0° C. The reaction mixture was left at 4° C. overnight. Water (100 ml) was added carefully to destroy excess boron tribromide. The solid precipitation was filtered off to yield brownish pure compound. Yield=4.15 g. (94%). 1H NMR (dmso-d6): 9.29 (s, 1H), 9.20 (s, 1H), 8.77 (s, 1H), 7.46 (d, 1H, J=3.02 Hz), 6.65 (d, 1H, J=8.89 Hz), 6.33 (dd, 1H, J=8.95 and 2.98 Hz), 4.35 (s, 2H). 13C NMR (dmso-d6): 165.0, 150.3, 150.2, 140.2, 126.6, 116.2, 111.6, 44.1. ES-HRMS [M+H]+202.0271. Calcd for (C8H9NO3):202.0278.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][N:3]=1.[OH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: COc1ccc(COc2cnc(Cl)n(C)c2=O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(COc2cnc(-c3cccc(O)c3)n(C)c2=O)cc1
Temperature: 120 °C
Yield: 14.1 %

Procedure:
To a solution of 2 g (7.12 mmol) 2-chloro-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one in 20 ml THF was added 521 mg (0.712 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct, 1.33 g (9.62 mmol) 3-hydroxyphenylboronic acid, and 11.4 ml (11.4 mmol) 1 M aq Cs2CO3. The reaction mixture was heated to 120° C. for 30 min in the microwave, then diluted with 10 ml water, extracted with 100 ml EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (50 g silica gel, 0-100% EtOAc:hexane) gave 340 mg (14% yield) of 2-(3-hydroxyphenyl)-5-[(4-methoxybenzyl)oxy]-3-methylpyrimidin-4(3H)-one. LCMS [M+H]+=339.0.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:21]2[CH2:22][CH2:23][CH:19]([O:18][C:17]3[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:28])[F:27])[CH:16]=3)[CH2:20]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: FC(F)(F)c1cccc(OC2CCNC2)c1
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 57.6 %

Procedure:
The title compound (D92) (270 mg) was prepared according to the experimental procedure described in Description 62 starting methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and from 3-(3-(trifluoromethyl)phenoxy)pyrrolidine (D58) (323 mg, 1.39 mmol).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CCN(CC)CC>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
A mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (4.18 g, 20.0 mmol), morpholine (2.09 g, 24.0 mmol), Et3N (6.07 g, 60.0 mmol) and EtOAc (30 mL) was stirred at rt for 5 h. The mixture was then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (5.0 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1OCc1ccccc1)OCc1ccccc1
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of (2-hydroxyphenyl)acetic acid (125 g) in dimethylformamide (1.9 l) was added potassium carbonate (909 g) and benzyl bromide (281 g) successively. After being stirred for 18 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1N aqueous sodium hydroxide solution and brine, dried and evaporated in vacuo. Dichloromethane was added to the residue and the solution was treated with activated carbon. The mixture was filtered and evaporated to give benzyl (2-benzyloxyphenyl)acetate (132 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1>[Pd].C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)nc1N
Reaction time: 1 h
Yield: 122.7 %

Procedure:
2 g of 2-amino-3-nitro-6-(pyrrolidin-1-yl)pyridine, synthesized according to the above procedure, 100 ml of ethanol and 0.5 g of palladium-on-charcoal are charged to a 300 ml autoclave. The mixture is reduced for one hour at a pressure of 8 bar with stirring. The catalyst is subsequently removed by filtration and then the filtrate is acidified with hydrochloric acid. After diluting with diisopropyl ether, the precipitate formed is filtered off and dried. 2.1 g of powder are obtained, Yd=87.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=1.[CH3:29][N:30]([CH2:38][CH:39]=O)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C(O)(=O)C.C([BH3-])#N.[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH2:16][NH:17][CH2:39][CH2:38][N:30]([CH3:29])[C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[N:11]=[C:10]([C:21]([F:23])([F:24])[F:22])[CH:9]=1
Reactant: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(C#N)c1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccccc1CCOc1cc(C(F)(F)F)nn1-c1cccc(CNCCN(C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
To a solution of 131 (85 mg, 0.219 mmol) in THF (0.4 mL) at 0° C. under nitrogen was added BH3 in THF (1.114 mL, 1.0M solution, 1.114 mmol). The reaction was stirred at room temperature for 1 hour then it was cooled to at 0° C. and quenched carefully with methanol. The mixture was concentrated, MeOH (1.5 mL), tert-butyl methyl(2-oxoethyl)carbamate (38.0 mg, 0.219 mmol) and acetic acid (25.1 μL, 0.439 mmol) were added and the mixture was stirred at room temperature for 1 h after which sodium cyanoborohydride (34.5 mg, 0.549 mmol) was added. After 16 h, the reaction was worked-up as usual and the residue was purified by silica gel chromatography (Biotage 12M, 0-5% MeOH/DCM) to give 132 (29.3 mg, 0.053 mmol, 24.34% yield) as clear oil. LRMS(ESI): (calc.) 548.6 (found) 549.2 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.Cl.Br[C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:23]([CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[C:22]([CH2:32][O:33][CH2:34][CH3:35])=[N:21][C:15]=3[C:16]([NH2:20])=[N:17][C:18]=2[CH:19]=1.B1([C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)OCCCO1.O>C1(C)C=CC=CC=1.C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:34]([O:33][CH2:32][C:22]1[N:23]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[CH:19][C:18]=3[N:17]=[C:16]([NH2:20])[C:15]=2[N:21]=1)[CH3:35]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCN1CCNCC1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCO
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCN1CCNCC1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (0.0409 g, 0.156 mmol), 2 M aqueous sodium carbonate (18.3 mL, 36.5 mmol) and a solution of palladium (II) acetate (0.0117 g, 0.52 mmol) in warm toluene were added to a solution of 7-bromo-2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (5.28 g, 10.4 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.87 g, 11.5 mmol) in n-propanol (8 mL). The reaction was heated at reflux under nitrogen for three hours then allowed to cool to ambient temperature. Deionized water was added, and organic solvent was removed under reduced pressure. The aqueous mixture was extracted with ethyl acetate (3×), and the combined organic fractions were washed sequentially with 2 M aqueous sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was combined with material from another run and purified by flash column chromatography on silica gel (eluting with chloroform:methanol in a gradient from 90:10 to 50:50 and 50:50 chloroform:CMA) to provide 3.54 g of 2-ethoxymethyl-1-(2-piperazin-1-ylethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 208-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([F:23])=[C:19]([F:22])[CH:20]=2)[C:15](=[O:24])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13]1>C(O)(=O)C.[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([F:23])=[C:19]([F:22])[CH:20]=3)[C:15](=[O:24])[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13]2)[C:2]([F:1])=[CH:7][C:6]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
Ethyl 1-(2,4-difluoro-5-nitrophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (3.7 grams) was dissolved in 60 ml of acetic acid, to which was added 400 mg of 10% palladium on carbon. Under a hydrogen atmosphere, the solution was stirred for 2 days at room temperature. The catalyst was removed by a membrane filter and the filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 2.9 g of the title compound.
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:28])[C:14]2[C:19]([S:20][CH3:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[O:26][CH3:27])[CH2:3]1.COCCN(S(F)(F)[F:39])CCOC>>[F:39][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:28])[C:14]2[C:19]([S:20][CH3:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[O:26][CH3:27])[CH2:3]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(O)C1
Reactant: COCCN(CCOC)S(F)(F)F
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(F)C1

Procedure:
The title compound, light yellow solid, MS: m/e=421.1 [(M+H)+], was prepared in accordance with the general method of example 17 from N-[(1RS,2SR)-2-(3-hydroxy-pyrrolidin-1-yl)-cyclopentyl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 63) and bis(2-methoxyethyl)aminosulfur trifluoride. The two diastereomers were not separated.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][C:3]1=[O:39]>C(O)(=O)C.[Zn]>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:19]2([CH2:18][O:17][CH:15]([C:6]3[CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=[C:10]4[C:5]=3[NH:4][C:3](=[O:39])[CH2:2]4)[CH3:16])[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:21][CH2:20]2)=[CH:33][CH:34]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c1NC(=O)C2
Yield: 62.5 %

Procedure:
To a solution of tert-butyl 4-((1-(3,3-dibromo-2-oxo-5-(trifluoromethyl)indolin-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (27.9 mg, 0.040 mmol) in acetic acid (500 μL) cooled briefly in a cold water bath was added zinc dust <10 micron (18 mg, 0.275 mmol). TLC (30% ethyl acetate/hexanes) after 15 minutes showed complete conversion of starting material. After 45 minutes the mixture was filtered through celite with ethyl acetate and concentrated. The crude material was purified on SiO2 eluting with 30% ethyl acetate/hexanes to give the product (13.3 mg, 0.025 mmol, 62%) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 7.55-7.62 (m, 2H), 7.32 (s, 1H), 7.20-7.28 (m, 2H), 7.11 (s, 1H), 7.04 (t, J=8.69 Hz, 2H), 4.28 (q, J=6.55 Hz, 1H), 3.64-3.81 (m, 2H), 3.42 (s, 2H), 3.23-3.36 (m 2H), 2.88-3.08 (m, 2H), 2.16-2.25 (m, 1H), 2.04-2.12 (m, 1H), 1.67-1.85 (m, 1H), 1.57-1.64 (m, 1H), 1.42 (s, 9H), 1.29 (d, J=6.55 Hz, 3H); Mass spec. (M-H)−: 535.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].S(=O)(=O)(O)O.O.[Br:18]([O-])(=O)=O.[K+]>C(O)(=O)C>[Br:18][C:6]1[C:5]([CH3:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-nitro-m-xylene (0.96 g, 6.4 mmol) in acetic acid (8 mL) and sulfuric acid (4 g) and Water (4 mL) was added potassium bromate (1.18 g, 7 mmol) portion-wise over 20 minutes. The mixture was allowed to stir 72 hours at room temperature. The desired product was recovered together with starting material after partition between water, and ethyl acetate (2×) washing with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, decanted and upon concentration under reduced pressure yielded the desired 2-bromo-1,3-dimethyl-4-nitrobenzene and starting material as an oily solid. The crude mixture was carried on to step two without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.[CH2:28]=O>C(O)=O.O.CCOC(C)=O>[CH3:28][N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1
Reactant: C=O
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Solvent: O=CO
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.072 g) in formic acid (0.40 mL) and water (0.10 mL) was added 37% formaldehyde (0.050 mL). After 1 hour at reflux, the reaction mixture was diluted with EtOAc and the solution washed with aqueous NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated to yield the titled compound (74.3 g). MS (m/z) 482 (MH+). mp 221° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:12]([O:14][CH:15]=[CH2:16])=[O:13]>CCOCC>[C:12](=[O:13])([O:14][CH:15]=[CH2:16])[O:4][CH2:3][CH2:2][Br:1]
Reactant: OCCBr
Reactant: C=COC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=COC(=O)OCCBr
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.8 %

Procedure:
To a 1L 4-neck round bottom flask fitted with a mechanical stirrer, thermometer, condenser, dropping funnel and nitrogen blanket was added 31.2 g (250 mmol) of 2-bromoethanol, 21.4 g (270 mmol) of pyridine and 400 mL of ether. The reaction was cooled with an ice-water bath to less than 10° C. then 28.8 g (270 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. The reaction was stirred to room temperature for 27 hours. Then the organics were washed twice with 2N HCl, twice with 2N NaOH, then dried over magnesium sulfate. The solvent was removed on a rotary. evaporator and the resulting oil was passed through a short silica gel column, to remove most of the color, to give 38.4 g (197 mmol, 78.8% yield). FTIR (neat, capillary) 3672.76, 3469.03, 3096.75, 2972.97, 2155.40, 2057.14, 1754.37, 1648.44, 1563.96, 1455.87, 1443.36, 1427.17, 1388.17, 1299.17, 1285.60, 1244.29, 1221.29, 1152.23, 1095.86, 1049.38, 988.10, 940.93, 897.08, 875.78, 828.81, 778.74, 738.01, 694.54, 663.28. NMR (CDCl3) 6.85-7.23 (1H,q), 4.40-5.10 (4H,m), 3.42-3.59 (2H,t).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](OB(O)O)=[CH:8][CH:7]=1.Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1.[F-].[Cs+]>COCCOC.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[CH:8][CH:7]=1
Reactant: COCOCc1ccc(OB(O)O)cc1
Reactant: Brc1nccs1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: COCOCc1ccc(-c2nccs2)cc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 46.5 %

Procedure:
To a solution of 1-bromo-4-[(methoxymethyloxy)methyl]benzene (3.0 g) in tetrahydrofuran (52 mL) was added n-butyllithium (1.6 mol/L hexane solution, 9.3 mL) at −78° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added triisopropyl borate (2.6 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g). A mixture of the obtained 4-[(methoxymethyloxy)methyl]phenylboric acid (2.5 g), 2-bromothiazole (1.2 g), cesium fluoride (2.2 g) and tetrakis (triphenylphosphine) palladium (0) (0.16 g) in 1,2-dimethoxyethane (40 mL), ethanol (10 mL) and water (10 mL) was stirred at 85° C. for 24 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1) to give 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g). To a solution of 2-{4-[(methoxymethyloxy)methyl]phenyl}thiazole (0.80 g) in ethanol (10 mL) was added 2 mol/L hydrochloric acid solution (5 mL), and the mixture was stirred at 50° C. for 5 hours. Concentrated hydrochloric acid (0.10 mL) was added to the mixture, and the mixture was stirred for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-(thiazol-2-yl)benzyl alcohol (0.33 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.Br[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(C(C)C)C(C)C)C>C(OCC)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CCCCBr
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCNc1ccc2c(c1)CCC2
Yield: 31.8 %

Procedure:
13.3 g of 5-aminoindane, 23.0 g of ethyl 5-bromovalerate and 14.2 g of ethyl diisopropylamine are stirred together for 12 hours at 50°. After addition of diethyl ether thereto, the resulting precipitate is filtered off, the solvent is removed, and all volatile components are distilled off from the residue at 50° under a pressure of 10-2 mm Hg. The residue (which is left) is recrystallized from petrol ether to obtain 8.3 g (55.7% of theory) of ethyl 5-(indan-5-ylamino)valerate, MP 61° to 63°.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH2:9][Br:11])=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(Br)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)c(Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:66]=[CH:65][C:61]([C:62]([OH:64])=[O:63])=[CH:60][CH:59]=2)[N:57]=1>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:59]=[CH:60][C:61]([C:62]([OH:64])=[O:63])=[CH:65][CH:66]=2)[N:57]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-ProOH (0.56 g, 2.2 mmol) and HATU (2.2 mmol, 0.83 g) were combined in 35 mL of DMF. To this solution was added DIEA (2.4 mmol, 0.42 mL). This solution was stirred at room temperature for 1 hr. 4-(2-Amino-thiazol-4-yl)-benzoic acid (2.2 mmol, 0.5 g) was then added to the solution. The reaction mixture was stirred at 70° C. overnight. It was brought to room temperature and then evaporated to dryness. The crude was purified using reverse phase HPLC. MS: 452.1 (M+H+)