Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](O)[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([Cl:25])[CH:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[N:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ON1C(c2ccc(Br)cc2)=CC=NC1c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(F)c1C1N=CC=C(c2ccc(Br)cc2)N1Cl
Temperature: 110 °C
Reaction time: 1 h

Procedure:
23.2 g of 4-(4-bromophenyl)-2-(2,6-difluorophenyl)-3-hydroxypyrimidine and 100 ml of POCl3 are mixed and stirred for one hour at 110° C. The reaction mixture is slowly poured into a solution of 250 g of NaOH (solid) in water, and filtered. After dissolving the precipitate in ethyl acetate, drying with magnesium sulfate, filtering and concentrating, the title compound is obtained with a melting point of 146-148° C. (compound 3.354).
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4]([CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH3:6])[CH3:5].[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[N:13]1([CH2:2][C:3](=[O:12])[C:4]([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)([CH3:6])[CH3:5])[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C(=O)CCl)C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C(=O)Cn1cncn1)C1OCCO1
Yield: 71.5 %

Procedure:
180.6 g (0.94 mol) of 1-chloro-3-(dioxolan-2-yl)-3-methyl-butan-2-one, 64.9 g (0.94 mol) of 1,2,4-triazole and 142.7 g (1 mol) of potassium carbonate in 1,000 ml of methyl ethyl ketone are heated under reflux for 16 hours. The solid is filtered off under suction and the solvent is distilled off, the oily residue is taken up in 700 ml of methylene chloride, and the organic phase is extracted with twice 1,000 ml of water. The solvent is distilled off from the organic phase. 151.3 g (71.5% of theory) of 1-(1,2,4-triazol-1-yl)-3-(dioxolan-2-yl)-3-methyl-butan-2-one are obtained as an oil with a purity of 99% according to gas chromatography. ##STR23##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH2:44]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCC1OCCO1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3OCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and C-[1,3]dioxolan-2-yl-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.61 (m, 6 H), 3.27-3.30 (m, 4 H), 3.60-3.89 (m, 6 H), 4.70-4.89 (bd, 1 H), 6.20-6.34 (bd, 1 H), 6.94-6.99 (m, 1 H), 7.14-7.21 (m, 2 H), 7.40 (d, J=8.0 Hz, 1 H), 7.44 (s, 1 H), 7.52-7.61 (m, 3 H), 7.81 (d, J=7.3 Hz, 1 H), 7.96-7.98 (m, 1 H), 8.21 (s, 1 H), 10.42 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CC(C)([O-])C.[K+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CN(C)C=O>[NH2:7][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([F:12])=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc(C=O)cc2)c(F)cc1[N+](=O)[O-]
Yield: 85.1 %

Procedure:
A solution of 5-chloro-4-fluoro-2-nitroaniline (0.380 g, 1.99 mmol), potassium t-butoxide (0.269 g, 2.39 mmol), and 4-hydroxybenzaldehyde (0.292 g, 2.39 mmol) in dimethylformamide (5 mL) was heated to 80 degrees Centigrade for 6 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed one time in brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-30% ethyl acetate/hexanes eluted the product to give 0.468 g of 4-[(5-amino-2-fluoro-4-nitrophenyl)oxy]benzaldehyde as an orange solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1.CCN(CC)CC>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:15]([N+:29]([O-:31])=[O:30])[CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc(N)c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(NC(=O)OCc2ccccc2)c2ccccc12
Yield: 26.2 %

Procedure:
Benzyl chloroformate (1.56 mL, 10.94 mmol) was added to a solution of ethyl (4-amino-2-nitronaphthalen-1-yl)acetate (1.0 g, 3.65 mmoml) and Et3N (0.56 mL, 4.01 mmol) in dry CH2Cl2 (20 mL) slowly that was at 0° C. under N2 atmosphere. The mixture was heated to reflux for 3 days and concentrated. The residue was dissolved in AcOEt (50 mL), and washed with H2O (10 mL) and saturated aqueous NaCl (25 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (20% AcOEt-Petroleum ether to CHCl3) afforded ethyl [4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]acetate (0.39 g, 26%) as an orange solid. M.p. 160-164° C.; 1H NMR (CDCl3, 500 MHz) δ 8.09 (d, 8.5, 1H), 7.88 (d, 8.0, 1H), 7.66 (t, 8.0, 1H), 7.60 (t, 7.0, 1H), 7.46 (d, 7.5, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 7.07 (s, 1H), 4.92 (brs, 1H), 4.52 (d, 4.0, 2H), 4.24 (s, 2H), 4.19 (q, 7.0, 2H), 1.26 (t, 7.5, 3H); IR (neat) 3397, 2927, 1723, 1594, 1537, 1515, 1439, 1333, 1200, 1124, 1027, 823, 752, 703 cm−1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].[C:9](=S)=[S:10]>CCO>[NH:7]1[C:3]2[C:2](=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[C:9]1[SH:10]
Reactant: S=C=S
Reactant: Nc1cccnc1N
Solvent: CCO
Product: Sc1nc2ncccc2[nH]1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
To a solution of pyridine-2,3-diamine (5 g) in EtOH (150 mL) was added carbon disulfide (23 mL) at room temperature. The mixture was stirred at 40° C. under Ar for 10 h. The mixture was cooled to room temperature. The resulting white solid was filtered and washed with ether to give 1H-imidazo[4,5-b]pyridine-2-thiol (5.61 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]2[C:9]([CH2:10][OH:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[CH3:1][C:2]1[N:3]2[C:9]([CH:10]=[O:11])=[CH:8][N:7]=[C:4]2[S:5][CH:6]=1
Reactant: Cc1csc2ncc(CO)n12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1csc2ncc(C=O)n12
Yield: 22.7 %

Procedure:
A solution of 3-Methylimidazo[2,1-b]thiazole-5-methanol (FIG. C-5) (0.9 g) in DMF (10 mL) was diluted with toluene (200 mL), treated with MnO2 (3.0), and azeotropically distilled for 1.5 hours. The suspension was filtered and the filtrate was concentrated to 10 mL. The concentrate was diluted with ice water and the precipitated 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (0.665 g) was filtered. An aliquot (225 mg) was recrystallized from ethyl acetate-hexane to yield pure 3-Methylimidazo[2,1-b]thiazole-5-carboxaldehyde (FIG. C-6) (202 mg), m.p. 163-165°.
Reaction SMILES: Cl.[CH2:2]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4].C(Cl)Cl.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C(N(CC)CC)C>[CH2:2]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:15](=[O:16])[CH:14]([Cl:18])[Cl:13])[CH:3]=[CH2:4]
Reactant: C=CCNCCCC
Reactant: O=C(Cl)C(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CCCC)C(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ten and five-tenths grams of allyl-n-butyl amine hydrochloride was added to 100 ml. of methylene chloride followed by 14.5 g. of triethylamine. The mixture was stirred in a water bath at room temperature while 10.4 g. of dichloroacetyl chloride was added dropwise, and stirring was continued for 30 minutes after addition was complete. The mixture was washed and the solvent stripped under vacuum. Yield was 13 g., nD30 1.4603. The intermediate was used without further purification to prepare Compound No. 12 (Example VII).
Reaction SMILES: [Br:1]Br.ClC(Cl)C.[CH3:7][O:8][CH:9]([O:20][CH3:21])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[CH3:19].[OH-].[Na+]>CO>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:9]([O:20][CH3:21])[O:8][CH3:7])=[C:13]([CH3:19])[C:14]=1[CH3:18]
Reactant: BrBr
Reactant: COC(COc1cccc(C)c1C)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COC(COc1ccc(Br)c(C)c1C)OC
Reaction time: 1 h
Yield: 92.1 %

Procedure:
Bromine (140 g) was added dropwise to a 760 ml of dichloroethane solution containing 180 g of 1-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene while stirring and cooling (ice bath) and maintaining the temperature of the reaction mixture not exceeding 10° C. After stirring for 30 minutes after completion of the addition, the reaction mixture was condensed under reduced pressure (a temperature of 40° C. or lower). The condensate was added dropwise in a solution comprising 37 g of sodium hydroxide dissolved in 185 g of methanol while stirring. Stirring was continued for one hour after completion of the addition, methanol was removed under reduced pressure, and 30 ml of dichloroethane and 570 ml of water were added to the residue and then the mixture was separated with each other. The organic layer was condensed under reduced pressure, a resulting brownish oil was distilled under reduced pressure to give 228 g of 1-bromo-4-(2,2-dimethoxyethoxy)-2,3-dimethylbenzene. Boiling point: 128° to 131° C./0.5 mmHg; Melting point: 40° to 41° C.; and Yield: 92%.
Reaction SMILES: C(N[C@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.[CH3:16][C:17]1[O:18]C(=O)C(=CC2C=CC=CC=2)[N:21]=1>O>[NH:21]([C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:6]=[CH:5][C:13]([OH:15])=[O:14])[C:17]([CH3:16])=[O:18]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC1=NC(=Cc2ccccc2)C(=O)O1
Solvent: O
Product: CC(=O)Nc1ccccc1C=CC(=O)O

Procedure:
In the process for the preparation of N-acetylphenylalanine by opening the ring of 2-methyl-4-benzylidene-1,3-oxazolin-5-one with water to give 2-acetaminocinnamic acid and subsequently catalytically hydrogenating the latter, both reaction stages are carried out in a mixture of an aliphatic C3 -ketone to C10 -ketone or a water-miscible ether and water as the solvent, and the hydrogenation of the 2-acetaminocinnamic acid is carried out at temperatures of 10° to 50° C. and pressures of 1 to 15 bar in the presence of a supported palladium catalyst.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[CH:27][C:26]=2[CH:31]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:31][C:26]=2[CH:27]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2cc(Br)ccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 90.1 %

Procedure:
According to the procedure of S. Gronowitz, et al., Synth. Commin., 6, (7), 475 (1976), to a stirred, boiling partial solution of N-bromosuccinimide (17.63 g, 0.099 mol) in CCl4 (200 mL) was added 2,2'-azobis-(2-methylpropionitrile) (1.1 g, 0.007 mol). After one minute, a solution of 5-bromo-2-methylbenzthiophene (15.0 g, 0.066 mol) in CCl4 (100 mL) was added. The resulting mixture was heated at reflux for 2 hours and cooled to 0° C. The solid was filtered. The filtrate was concentrated to give 18.19 g (90%) of product as an orange solid.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:26]([F:29])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:2]2[NH:3][C:4](=[O:11])[C:5]3[CH:10]=[CH:9][NH:8][C:6]=3[N:7]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2)OC1(C)C
Reactant: O=c1[nH]c(Cl)nc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)nc2[nH]ccc12
Temperature: 150 °C
Yield: 5.6 %

Procedure:
A microwave reaction vial was charged with 2-chloro-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (Intermediate F) (80 mg, 0.32 mmol), 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (154 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium(0) (27.3 mg, 0.024 mmol) and a 2M aqueous sodium carbonate solution (0.75 mL) in ethanol (3 mL). The vial was sealed and the reaction was heated in the microwave at 150° C. for 10 min. At this time, the resulting mixture was filtered through a pad of Celite® and concentrated in vacuo. Flash chromatography (30/1 methylene chloride/methanol) afforded 2-(4-trifluoromethyl-phenyl)-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one (5.0 mg, 3.8%) as a white solid. 1HNMR (400 MHz, DMSO-d6) δ ppm 6.50-6.59 (m, 1H) 7.9 (d, 2H) 7.11-7.19 (m, 1H) 8.3 (d, 2H) 12.1 (s, 1H) 12.3 (s, 1H). LC-MS calcd. for C13H9F3N3O [(M+H)+] 280, obsd. 279.9.
Reaction SMILES: C(OC(=O)O[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3Cl)C=C1)C.[Cl:23][C:24]1[N:32]=[C:31]2[C:27]([N:28]=[CH:29][N:30]2[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=[N:39]3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[C:26](NCC(C2C=CC=CC=2)C2C=CC=CC=2)[N:25]=1.[NH2:62][CH2:63][CH:64]([C:72]1[CH:77]=[CH:76][C:75]([OH:78])=[CH:74][CH:73]=1)[C:65]1[CH:70]=[CH:69][C:68]([OH:71])=[CH:67][CH:66]=1>>[OH:78][C:75]1[CH:76]=[CH:77][C:72]([CH:64]([C:65]2[CH:66]=[CH:67][C:68]([OH:71])=[CH:69][CH:70]=2)[CH2:63][NH:62][C:26]2[N:25]=[C:24]([Cl:23])[N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3[C@@H:33]2[CH2:37][C@H:36]([N:38]3[N:42]=[N:41][C:40]([CH2:43][CH3:44])=[N:39]3)[C@@H:35]([OH:45])[C@H:34]2[OH:46])=[CH:73][CH:74]=1
Reactant: NCC(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccc(O)cc5)c5ccc(O)cc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AC) using a procedure analogous to that of (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Intermediate BA6) by replacing 2,2-diphenylethylamine with 4,4′-(2-aminoethylidene)bis-phenol (second step b). MS (ES+) m/e 578.34 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)(=O)=O)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:32][C@H:33]4[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]4)[C:14]([F:21])=[CH:13][N:12]=3)=[CH:9][N:8]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)(=O)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-chloro-3-(5-fluoro-4-methylsulfonyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine, 1a, (3.5 g, 7.5 mmol) and tert-butyl (3S)-3-aminopiperidine-1-carboxylate (1.8 g, 9.0 mmol) in DMF (32 mL) was added diisopropylethylamine (2.6 mL, 15.1 mmol). The reaction mixture was heated at 90° C. for 75 minutes. The mixture was cooled to room temp and diluted into aqueous saturated NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO4), filtered and concentrated under vacuo. The resulting residue was purified via silica gel chromatography (0%-10% MeOH/CH2Cl2) to afford the desired product 1b as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
EX-628A) To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (50 g, 0.24 mol) and N-bromosuccinimide (42.75 g, 0.24 mol) in 100 mL of carbon tetrachloride under nitrogen was added 2,2′-azobisisobutyronitrile (0.71 g, 0.004 mol). The resultant mixture was refluxed for 2 h then cooled to room temperature and quenched with 300 mL of water. The organic layer was collected, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 66.0 g (96%) of the desired crude 3-(1,1,2,2-tetrafluoroethoxy)bromomethylbenzene product as a yellow oil. 1H NMR indicates that this oil is a mixture of products: 7% dibrominated, 67% monobrominated, and 20% starting material. The crude product was used without further purification. ESMS m/z=287 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:29]=[CH:28][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=2)=[O:19])=[CH:16][CH:15]=1.[OH-].[Na+].O.O>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][S:1][C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=3)=[CH:22][CH:21]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: O=c1[nH]c(S)nc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CSc2nc3ccccc3c(=O)[nH]2)cc1
Yield: 80.3 %

Procedure:
A solution of 2-mercapto-4(3H)-quinazolinone (1.78 g), 4-(4-chlorobenzoyl)benzyl bromide (3.07 g) and 1N-sodium hydroxide/water (10.5 ml) in ethanol (20 ml) was stirred at room temperature for 30 minutes. To the reaction mixture was added water and the resulting precipitate was collected by filtration, washed with water, methanol and ethyl acetate, dried, and recrystallized from ethyl acetate to provide the title compound as colorless solid (3.24 g).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[I:6][C:7]1[C:8]([CH3:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][NH:13][C:12]2=O>>[Cl:3][C:12]1[C:11]2[C:16](=[C:7]([I:6])[C:8]([CH3:18])=[CH:9][CH:10]=2)[N:15]=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)[nH]cnc2c1I
Product: Cc1ccc2c(Cl)ncnc2c1I
Yield: 92.1 %

Procedure:
Phosphorous oxychloride (19.5 mL, 210 mmol) and 8-iodo-7-methylquinazolin-4(3H)-one (2.00 g, 6.99 mmol) were added to a round bottomed flask. The reaction mixture was heated at reflux for 2 h. Upon cooling, excess POCl3 was removed under reduced pressure and the remaining crude product dissolved in DCM (100 mL) and washed with ice-cold water (300 mL) to remove excess acid. The crude residue dissolved in DCM was then dried over anhydrous sodium sulfate and concentrated in vacuo to give 4-chloro-8-iodo-7-methylquinazoline (1.96 g, 92%) as an amorphous brown solid. MS (M+H)+ 305.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[C:12]([CH:14]3[C:20]4[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=4[CH:18]=[CH:17][C:16]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:15]3=4)[C:11](=[O:31])[NH:10][C:9]2=[O:32])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:34][O:35][C:36](=[O:42])[C@@H:37]1[CH2:41][CH2:40][CH2:39][NH:38]1>>[CH3:25][C:23]1[CH:22]=[CH:21][C:20]2[CH:14]([C:12]3[C:11](=[O:31])[NH:10][C:9](=[O:32])[N:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([N:38]5[CH2:39][CH2:40][CH2:41][C@H:37]5[C:36]([O:35][CH3:34])=[O:42])[N:7]=4)[CH:13]=3)[C:15]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:16]=3[CH:17]=[CH:18][C:19]=2[CH:24]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(Cl)n2)c(=O)[nH]c1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1c1nccc(-n2cc(C3c4ccc(C)cc4C=Cc4cc(C)ccc43)c(=O)[nH]c2=O)n1

Procedure:
The subtitle compound was prepared from the product of example 8 step (ii) (0.3 g) and L-proline methyl ester hydrochloride (0.56 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 5% methanol in chloroform. Yield 0.3 g.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16]CC)=[O:15])=[CH:8][NH:9]3)=[CH:4][C:3]=2[O:2]1.[H-].[Na+].ClC(Cl)(Cl)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CN(C)C=O>[CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6](=[O:19])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2cc3c(cc2c1=O)OCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC(F)(F)F)c2cc3c(cc2c1=O)OCO3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 15.6 (0.06 mole) of 6,7-methylenedioxy-4(1H)-quinolone-3-carboxylic acid, ethyl ester (J. Med. Chem. 11, 160 (1968)) and 1.5 g. (0.062 mole) of sodium hydride powder in 250 ml. of dimethyl formamide was heated with stirring for 0.5 hour at 80°-90° C. 2,2,2-Trifluoroethyl trichloromethanesulfonate (17.5 g. 0.62 mole) was then added dropwise. The temperature is maintained at 80°-90° for an additional 2 hours. The cooled mixture was poured into ice water and the solid product was isolated by filtration. It was recrystallized from ethanol. This product was identical to that obtained from Example 4.