Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH:12]([OH:23])[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[NH:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:24]1[CH:28]=[CH:27][C:26]([NH:29][CH2:18][C:17]2[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=2)[O:14][CH2:13][CH:12]([OH:23])[CH2:11][N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[N:25]1
Reactant: O=Cc1cccc(OCC(O)CN2CCc3ccccc3C2)c1
Reactant: Nc1cc[nH]n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OC(COc1cccc(CNc2cc[nH]n2)c1)CN1CCc2ccccc2C1
Temperature: 60 °C
Yield: 11 %

Procedure:
To a solution of 3-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropoxy)benzaldehyde (200 mg, 0.64 mmol) in DCM (15 mL) was added 1H-pyrazol-3-amine (80 mg, 0.96 mmol). The solution was heated at 60° C. for 0.5 h. NaBH(OAc)3 (204 mg, 0.96 mmol) was then added into the reaction mixture which was heated at 60° C. for another 1 h. The reaction mixture was quenched by adding 1N HCl aqueous solution and diluted with DCM and washed with NaHCO3 aqueous solution. The separated organic layer was concentrated and the crude product was purified by preparative HPLC purification. (26 mg, yield 11%). MS (ESI+) e/z: 379.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.33-7.18 (m, 7H), 7.00-6.96 (m, 2H), 6.84-6.80 (m, 1H), 4.48-4.44 (m, 3H), 4.28 (s, 1H), 4.06-3.98 (m, 2H), 3.59-3.56 (m, 2H), 3.42-3.39 (m, 2H), 3.20-3.15 (m, 2H).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:16])[CH:7]=1>CO>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([O:12][CH3:1])=[O:11])=[C:8]([CH3:16])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(=O)O)c(C)cc1O
Solvent: CO
Product: COC(=O)c1cc(C)c(O)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Acetyl chloride (0.107 mL) was added dropwise to a solution of 4-hydroxy-2,5-dimethylbenzoic acid (example 18, step a) (0.249 g) in methanol (15 mL) and the resulting mixture stirred at room temperature for 72 h. Acetyl chloride (0.107 mL) was then added and the reaction heated to 50° C. and stirred at this temperature overnight. The reaction was concentrated and the residue purified by silica gel chromatography eluting with 1:1 isohexane:ethyl acetate to 100% ethyl acetate gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a white solid. Yield 0.25 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].ClCCl>C(N(CC)CC)C>[CH:23]([S:24]([NH:1][CH2:2][C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)(=[O:26])=[O:25])=[CH2:22]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1c(-c2ccccc2)oc2c(CN)cccc2c1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NCc1cccc2c(=O)c(C)c(-c3ccccc3)oc12

Procedure:
This compound can be prepared by reacting Intermediate XXIV with 2-chloroethylsulfonylchloride in an halogenated solvent (e.g., dichloromethane) in presence of triethylamine at 0°-40° C., according to A. A. Goldberg, Jr., J. Chem. Soc., 464 (1945).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:13][CH:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:15](=[O:16])[CH:14]([CH3:13])[CH2:18][CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)C(=O)Cl
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of t-butyl alcohol (40.7 g, 549 mmol), Et3N (70 mL, 505 mmol), and DMAP (0.366 mL, 3 mmol) in anhydrous CH2Cl2 (100 mL) at 0° C. was added 2-methyl-butyryl chloride (38 g from step 1). The reaction was stirred at 0° C. for 2 h and then room temperature overnight. The cloudy reaction mixture was filtered through celite and concentrated. The residue was diluted with Et2O and washed with 0.1 N HCl. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was distillated at ˜100° C. bath temperature under weak in-house vacuum twice to give the desired 2-methyl-butyric acid tert-butyl ester 2-2 as a clear oil (42 g, ˜85% purity by 1HNMR analysis). 1HNMR (CDCl3, 500 Hz): 2.28-2.20 (m 1H), 1.68-1.56 (m, 1H), 1.44 (s, 9H), 1.46-1.37 (m, 1H), 1.44 (s, 9H), 1.09 (d, J=7.0 hz, 3H), 0.9 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Na].[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.BrC[C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C1C=CC=CC=1>[O:3]=[C:2]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6])[CH2:1][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:20]([C:19]1[CH:18]=[CH:17][CH:30]=[CH:29][CH:28]=1)=[O:21]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC[O-]
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: [Na+]
Agent: [Na]
Solvent: c1ccccc1
Product: CCOC(=O)C(C)C(=O)Cc1cccc(C(=O)c2ccccc2)c1
Temperature: 100 °C

Procedure:
Dry sodium ethylate prepared from 2.51 g of sodium was added to 125 ml of anhydrous benzene and 13.5 ml of ethyl acetylacetate at 20° C and after heating at 100° C for 15 minutes, 27.5 g of 3-bromomethyl-benzophenone were added all at once. The reaction mixture was refluxed for 3 hours and after cooling to 20° C, the benzene solution was washed twice with 25 ml of 2N hydrochloric acid and then with water until the wash water was neutral. The solution was dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 33.8 g of raw product which was chromatographed over silica gel and was eluted with a 50-50 mixture of ether-petroleum ether (B.P. of 40°-60° C) to obtain 15.3 g of 3-(2'-oxo-3'-ethoxycarbonyl-butyl)-benzophenone in the form of a marron resin which was used as is for the next step.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32]>C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][CH2:30][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[N:10]=[CH:9]1
Reactant: O=C(CBr)c1ccccc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Product: O=C(COCCCc1c[nH]cn1)c1ccccc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 5 mmol of 2-bromo-1-phenylethanone are stirred for 72 hours in methylene chloride. The solvent is evaporated off under reduced pressure and the residue is refluxed for 1 hour in 30 ml of 2N HCl and 30 ml of acetone. The solvent is evaporated off under reduced pressure and triphenylmethanol is extracted using diethyl ether. The aqueous phase is alkalized with ammonia, and the crude product is extracted with diethyl ether, purified by rotatory chromatography and crystallized as hydrogen maleate from diethyl ether and ethanol.
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH2:37].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][C:30]1([CH3:38])[CH2:34][CH2:33][CH2:32][N:31]1[CH2:35][CH2:36][NH:37][C:6]([C:5]1[CH:9]=[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])[C:2]([CH3:1])=[N:3][CH:4]=1)=[O:8]
Reactant: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Reactant: CC1(C)CCCN1CCN
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: Cc1ncc(C(=O)NCCN2CCCC2(C)C)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-Methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (6.6 g, 1.1 equiv) and 2-(2,2-dimethylpyrrolidin-1-yl)ethanamine (2.397 g, 11.14 mmol) were combined in DMF (100 ml) and treated with DIPEA (8.34 ml, 47.7 mmol) followed by HATU (4.44 g, 11.67 mmol). After stirring at RT for 90 mins, the mixture was partitioned between water (1 L) and EtOAc (750 ml). The resulting suspension was removed by filtration and the organic portion was washed with aqueous sodium bicarbonate, 0.5M lithium chloride, brine, dried MgSO4, filtered and evaporated to dryness. Purification by chromatography on silica eluting with 0-20% 2M NH3 in MeOH/TBME afforded residue which was recrystallised from acetone to afford the title compound;
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH2:16]([N:20]=[C:21]=[O:22])[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>CC(C)=O>[I:1][C:2]1[C:3]([S:12]([NH:15][C:21]([NH:20][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22])(=[O:14])=[O:13])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCCCN=C=O
Reactant: COC(=O)c1cccc(S(N)(=O)=O)c1I
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCNC(=O)NS(=O)(=O)c1cccc(C(=O)OC)c1I
Temperature: 25 °C

Procedure:
27.3 g of 2-iodo-3-methoxycarbonylbenzenesulfonamide and 9.0 ml of n-butyl isocyanate in 300 ml of absolute acetone are treated with 12 ml of DBU at room temperature and heated at the boil for 3 hours. The reaction solution is cooled to room temperature, concentrated to approximately 1/3 of its volume and poured into 1 l of water. The aqueous phase is acidified with concentrated hydrochloric acid to a pH of 1-2, and the precipitate obtained is filtered off with suction. 31.3 g of methyl 2-iodo-[[[(n-butylamino)carbonyl]amino]sulfonyl]benzoate of melting point 163°-7° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[S:44]1[CH:48]=[CH:47][N:46]=[C:45]1[C@@H:49]([NH2:51])[CH3:50]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][C@H:49]([C:45]2[S:44][CH:48]=[CH:47][N:46]=2)[CH3:50])=[O:42])=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3OC)c2cc1OC
Reactant: C[C@H](N)c1nccs1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4nccs4)cc3OC)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methoxyaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of (1S)-1-(1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (31 mg, yield 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.N1([C:20](N2C=NC=N2)=[O:21])C=NC=N1.[CH3:27][O:28][CH:29]([O:47][CH3:48])[C:30]1[C:39]([N:40]2[CH2:44][CH2:43][CH:42]([CH3:45])[C:41]2=[O:46])=[CH:38][C:37]2[CH2:36][CH2:35][CH2:34][NH:33][C:32]=2[N:31]=1>CN(C=O)C>[C:6]([C:5]1[C:8]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:9][C:2]([NH:1][C:20]([N:33]2[C:32]3[C:37](=[CH:38][C:39]([N:40]4[CH2:44][CH2:43][CH:42]([CH3:45])[C:41]4=[O:46])=[C:30]([CH:29]([O:28][CH3:27])[O:47][CH3:48])[N:31]=3)[CH2:36][CH2:35][CH2:34]2)=[O:21])=[N:3][CH:4]=1)#[N:7]
Reactant: COC(OC)c1nc2c(cc1N1CCC(C)C1=O)CCCN2
Reactant: O=C(n1cncn1)n1cncn1
Reactant: COCCNc1cc(N)ncc1C#N
Solvent: CN(C)C=O
Product: COCCNc1cc(NC(=O)N2CCCc3cc(N4CCC(C)C4=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 0 °C
Reaction time: 21 h

Procedure:
A solution of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (intermediate 75, 81 mg, 0.422 mmol) in anhydrous DMF (0.5 ml) was added drop wise to a mixture of di(1H-1,2,4-triazol-1-yl)methanone (77 mg, 0.422 mmol) and DMF (0.5 ml) cooled at 0° C. After stirring for 2 h at 0° C. a solution of (racemic) 1-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-3-methylpyrrolidin-2-one (intermediate 331, 68 mg, 0.212 mmol) in DMF (0.5 ml) was added. The suspension was allowed to warm to room temperature, was continued to stir for 21 h and quenched by the addition of MeOH. The reaction mixture was diluted with EtOAc, phases were separated and the water phase was extracted with EtOAc. The combined organic phases were washed with water and brine, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (0-5%) in DCM. Fractions containing the product were combined, concentrated and dried to yield the title compound as a colorless residue. (UPLC-MS 3) tR 0.96 min, ESI-MS 524.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH2:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].O>CN(C=O)C>[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]=[S:10]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOCCN
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCN=C=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2-methoxyethoxyl)ethanamine (0.820 g, 6.88 mmol) in DMF (69 mL) at 0° C. was added dropwise a solution of 1,1′-thiocarbonyldiimidazole (1.349 g, 7.57 mmol) in 21 mL of DMF. The mixture was warmed to RT and stirred for 90 min. The mixture was poured into water (130 mL) and extracted with Et2O (70 mL). The Et2O layer was washed with water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.) to afford 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (0.678 g, 4.21 mmol, 61% yield) as a yellow oil. The crude material was used in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O[CH:20]([CH:22]=[CH2:23])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([C:12]([CH2:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])([CH2:21]/[CH:20]=[CH:22]/[CH3:23])[CH:13]=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(C=O)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C/C=C/CC(C=O)(CCCC)CS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2-(((4-chlorophenyl)-sulfonyl)methyl)hexanal (3.38 g, 11.73 mmol) in 30 ml of toluene in a RBF fitted with a Dean-Stark trap is added 2-hydroxy-3-butene (5 mL, 57.73 mmol), followed by p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. The mixture is heated to reflux for 20 hours. After cooling to room temperature, the toluene solution is diluted with 10 mL of ethyl acetate and washed with 10 mL of saturated NaHCO3 solution. The aqueous phase is extracted with ethyl acetate. The combined organic extract is washed with water (2×10 mL), brine (1×10 mL), and dried with MgSO4. After removing solvents, the product is obtained as a brownish oil in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1.Br[C:20]1[N:24]2[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:17][C:16]1[C:11]([C:3]2[CH:4]=[C:5]([C:20]3[N:24]4[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[N:28][C:23]4=[N:22][CH:21]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ncc(F)cc2F)c1
Product: Fc1cnc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c(F)c1

Procedure:
4-Fluoro-3-(3,5-difluoropyridin-2-yl)phenylboronic acid was coupled with 3-bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine by the method of Example 78. Purification by chromatography on silica gel eluting with dichloromethane containing 2% methanol and crystallisation from toluene/isohexane gave 3-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine: δH (400 MHz, CDCl3) 8.80 (1H, d, J 7), 8.50 (1H, d, J 2), 8.12 (1H, s), 7.79 (1H, dd, J 7 and 2), 7.64 (1H, m), 7.36-7.43 (2H, m), 7.26 (1H, d, J 7); m/z (ES+) 395 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([S:33]([OH:36])(=[O:35])=[O:34])[CH:18]=[C:19]3[C:24]=2[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:31])=[O:30])=[CH:20]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+]>[Pd].O>[NH2:1][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([S:33]([OH:36])(=[O:35])=[O:34])[CH:18]=[C:19]3[C:24]=2[C:23]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:22][C:21]([S:29]([OH:32])(=[O:30])=[O:31])=[CH:20]3)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Agent: [Pd]
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: O
Product: Cc1cc(N)ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 20.0 g of 8-(5-nitro-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt, 90.0 ml of water and 2.0 g of 10% palladium on carbon catalyst is hydrogenated as described in Example 1. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated. The residue is dissolved in a minimum amount of water, then is added dropwise to 800 ml of stirred absolute ethanol. The mixture is stirred for 2 hours and allowed to stand for 48 hours. A light yellow solid is collected, washed with ethanol and ether, then is dried to yield 15.0 g of 8-(5-amino-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.CN([CH:42]=[O:43])C>C1COCC1.O>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:42]([OH:43])[N:7]([C:8]([CH3:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CC(C)(NC(=O)c1cccc(Cl)c1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2cccc(Cl)c2C1O
Reaction time: 2.5 h
Yield: 88.8 %

Procedure:
3-Chloro-N-(1-methyl-1-phenylethyl)benzamide (7.00 g, 25.6 mmol) was dissolved in THF (280 mL), and the solution was added with TMEDA (12.4 mL, 81.9 mmol), then added with sec-butyllithium-hexane solution (0.99 mol/L, 82.7 mL, 81.9 mmol) by drops at −78° C. for 40 minutes under argon atmosphere, followed by stirring at the same temperature for 2.5 hours. Then, the mixture was added with DMF (4.36 mL, 56.3 mmol) and warmed from −78° C. to room temperature over 2 hours. The reaction mixture was added with water, extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using diisopropyl ether to obtain 4-chloro-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (6.86 g, yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](Cl)(C)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br

Procedure:
A solution of 2-bromo-5-methylbenzoic acid (10 g) in trimethylsilyl chloride (30 ml) and methanol (100 ml) was stirred at room temperature overnight and evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, dried (MgSO4) and evaporated. Yield 10.1 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[Cl:15][C:16]1[C:24]2[NH:23][N:22]=[CH:21][C:20]=2[C:19]2[CH2:25][N:26]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:27](=[O:50])[C@@H:28]([CH2:30][C:31](=[O:49])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:29][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[C:24]2[NH:23][N:22]=[CH:21][C:20]=2[C:19]2[CH2:25][N:26]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[C:27](=[O:50])[C@H:28]([CH2:30][C:31]([N:12]3[CH2:11][CH2:10][CH:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[CH2:14][CH2:13]3)=[O:49])[CH2:29][C:18]=2[CH:17]=1
Reactant: Clc1ccc(C2CCNCC2)c(Cl)c1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3ccc(Cl)cc3Cl)CC2)C1=O
Yield: 40 %

Procedure:
4-(2,4-Dichlorophenyl)-piperidine (32 mg, 0.0.8 mmol) and [4-chloro-9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(S)-cyclohepta[e]inden-7-yl]acetic acid (25 mg, 0.07 mmol) were combined in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(R)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Title compound was obtained as off-white solid in 40% yield. High resolution MS m/e (M+H)+=575.1747.
Reaction SMILES: [C:1](=S)([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)C1C=CC=CC=1.Br.C(SCC1C=CC=CC=1)(=N)C1C=CC=CC=1.N1C=CC=CC=1.[NH2:41][CH:42]([C:48]#[N:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1COCC1.C(Cl)(Cl)Cl>[NH2:49][C:48]1[NH:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:41][C:42]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(N)C#N
Agent: Br
Agent: BrCc1ccccc1
Agent: N=C(SCc1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccccc2)[nH]c1N
Temperature: 25 °C
Yield: 69.2 %

Procedure:
Benzothioamide (1.37 g, 10 mmol) and benzylbromide (1.71 g, 10 mmol) in dry THF were heated to 60° C. for 2 h. After it was allowed to cool to room temperature, the reaction mixture was filtered. The desired benzyl benzimidothioate hydrobromide as a white solid (2 g, 65%) without further purification. To a solution of benzyl benzimidothioate hydrobromide (1.54 g, 5 mmol) in dry CHCl3 was added in one portion dry pyridine (5 mmol) at ambient temperature followed by ethyl 2-amino-2-cyanoacetate (0.64 g, 5 mmol). The reaction mixture was then heated to 65° C. for 2 h. After cooling to room temperature, the mixture was filtered to give the ethyl 5-amino-2-phenyl-1H-imidazole-4-carboxylate as a yellow colored solid (0.8 g, 68%). This solid (0.46 g, 2 mmol) was added with dry THF, Boc2O (0.87 g, 4 mmol), DMAP (24 mg, 0.2 mmol). The reaction was heated to 65° C. for 5 h. The solvent was evaporated in vacuo to give crude product. This crude product was then dissolved in MeOH—H2O (30 mL, 1:1) and LiOH was added in one portion. The reaction mixture was heated at 70° C. until starting material disappeared by TLC (˜4 h). The mixture was then cooled to ˜0-4° C. and 1N aq HCl was added cautiously dropwise until pH ˜5. The resulted mixture was extracted with DCM (3×20 mL). Combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC. The desired product 5-(tert-butoxycarbonylamino)-2-phenyl-1H-imidazole-4-carboxylic acid was obtained as white solid (0.1 g, 16%). 1H-NMR (DMSO, 500 MHz) δ (ppm): 9.01 (s, 1H), 8.05 (s, 2H), 7.35-7.42 (m, 3H), 1.45 (s, 9H); MS (ESI) m/z: 304 [M+H+].