Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH2:15][CH3:16])[CH:11]=[CH:12]2)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6](=[O:20])[C:5]3=[CH:4][C:3]=1[F:21].[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>CS(C)=O>[F:21][C:3]1[CH:4]=[C:5]2[C:14]3[N:9]([CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])[CH:10]([CH2:15][CH3:16])[CH:11]=[CH:12][C:13]=3[C:2]=1[N:28]1[CH2:29][CH2:30][N:25]([CH:22]([CH3:24])[CH3:23])[CH2:26][CH2:27]1
Reactant: CCC1C=Cc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)N1CCNCC1
Solvent: CS(C)=O
Product: CCC1C=Cc2c(N3CCN(C(C)C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 8 h
Yield: 64.8 %

Procedure:
4.62 g (0.015 mole) of 8-chloro-9-fluoro-5-ethyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was suspended in 45 ml of dimethyl sulfoxide, 7.69 g (0.06 mole) of N-isopropylpiperazine was added thereto, and this mixture was stirred at 100°-110° C. for 8 hours. The resulting reaction solution was evaporated to dryness under reduced pressure. 40 ml of methanol was added to the resulting residue and this mixture was stirred. The insoluble matter was collected by filtration and recrystallized from ethanol to obtain 3.88 g (64.7% yield) of 9-fluoro-5-ethyl-8-(4-isopropyl-1-piperazinyl)-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in the form of pale-yellow crystals. These crystals had a melting point of 186°-195° C. (dec.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15]C)[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:14]([C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:15]
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M203) (204 mg, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (94 mg, 58%).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.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>[C:14]1([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Product: O=Cc1cc2ccccc2nc1-c1ccccc1
Yield: 90 %

Procedure:
A solution of 960 mg (5 mmol) of 2-chloroquinolin-3-carbaldehyde, 570 mg (0.5 mmol) of Pd(PPh3)4, and 1.2 g of benzeneboronic acid in a mixture of 7.5 ml of 2M aqueous sodium carbonate solution and 20 ml of dioxane was heated for 40 h to 95° C. It was extracted with ethyl acetate, and the organic layer was dried and evaporated. The residue was chromatographed on silica gel with a hexane/ethyl acetate gradient 98:2 to 90:10 to give 1.05 g (90%) of the title aldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>C(C(C)=O)C>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=1
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Fc1ccc(CCl)cc1
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccccc1NCc1ccc(F)cc1

Procedure:
56 g N-(4-fluorobenzyl) 2-nitroaniline are reduced in the presence of 34 g of 5% palladized charcoal into methanol (560 ml) using a stream of hydrogen at room temperature and normal pression. After achievement of the reaction, the mixture is washed with nitrogen, filtered on clay (Trade Mark Celite) and concentrated to dryness. The residue is recrystallized from isopropyl ether. The desired N-substituted phenylene diamine, is thus obtained recovered weight: 38.5 g. The starting material N-(4-fluorobenzyl) 2-nitroaniline is prepared by alkylating the 2-nitroaniline by means of 4-fluorobenzyl chloride in the methyl ethyl ketone.
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH:13]([N:20]1C(=O)C2C(=CC=CC=2)C1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])([CH3:6])[CH3:5]>C1COCC1.CO>[C:4]([O:8][C:9](=[O:31])[NH:10][CH2:11][CH2:12][CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)NCCC(c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Temperature: 65 °C

Procedure:
85% Hydrazine hydrate (5.1 mL, 74 mmol) was added to a solution of [3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-phenyl-propyl]-carbamic acid tert-butyl ester (2.8 g, 7.4 mmol) in THF (25 mL) and MeOH (25 mL). The resulting mixture was heated at 65° C. for 6 hours. Then the precipitate was filtered, and the filtrate was concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel (dichloromethane:MeOH, 100:1, 1% NH3H2O) to give (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester as an off-white solid. (Yield 1.7 g, 92%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39](Br)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH:33][S:34]([C:37]2[S:38][C:39]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:40][CH:41]=2)(=[O:36])=[O:35])[CH:27]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NCc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (pyridin-3-ylmethyl)-amide (example B.x) (example B.56) (167 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (132 mg, 43%). MS (ISN) 606.2 [(M−H)−]; mp 177° C.
Reaction SMILES: [C:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)(=O)[CH2:2][CH2:3][CH3:4].C(O)=O.[CH:20]([NH2:22])=[O:21]>CCOCC>[CH:20]([NH:22][CH:1]([C:6]1([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4])=[O:21]
Reactant: CCCC(=O)C1(c2ccc(Cl)cc2)CCC1
Reactant: NC=O
Solvent: O=CO
Solvent: CCOCC
Product: CCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the ketone produced as described above (21 g) and 98% formic acid (6 ml) was added over a period of one and a half hours to formamide (15 ml) at 160° C. After completion of the addition the temperature was raised to 180° to 185° C. and maintained in this range for five hours. The mixture was cooled and extracted with chloroform to yield a thick gum which on heating with petroluem ether (b.p. 60°-80°) gave a colourless solid which was recrystallised from petroleum ether (b.p. 60°-80°) to yield N-formyl-1-[1-(4-chlorophenyl)cyclobutyl]butylamine (m.p. 97.5° to 98.5° C.) (Formula I R1 =propyl; R2 =H; R3 =H; R4 =CHO; R5 =4-Cl; R6 =H).
Reaction SMILES: C(N[C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9])(=O)CC.[C:13](NC1C=C(C=CC=1)N)(=[O:17])CCC>>[NH2:9][C:8]1[CH:7]=[C:6]([O:17][CH3:13])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCC(=O)Nc1cccc(N)c1
Reactant: CCC(=O)Nc1cccc(N)c1
Product: COc1cccc(N)c1

Procedure:
m-propionylaminoaniline, m-butyrylaminoaniline or
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[CH3:12][S-:13].[Na+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([S:13][CH3:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.12 g, 5.96 mmol) in DMSO (8 mL), sodium thiomethoxide (0.500 g, 7.14 mmol) was added. The mixture was stirred at room temperature for 2 h. H2O was added to induce precipitation. The precipitate was collected and dried on vacuum to give 2-chloro-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine as a solid (0.90 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1)=[O:4].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33]>C1COCC1>[CH3:35][O:34][C:32](=[O:33])[CH2:31][NH:1][CH2:2][C:3](=[O:4])[NH:5][CH2:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[C:23]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[O:14])[S:10][CH:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CN)cs2)c(C(=O)C2CCCC2)c1
Solvent: C1CCOC1
Product: COC(=O)CNCC(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 36.1 %

Procedure:
{[({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-carbamoyl)-methyl]-amino}-acetic acid methyl ester (44 mg, 88%) was prepared by treating 2-amino-N-{2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-acetamide (104 mg, 0.25 mmol) with methyl bromoacetate (0.023 mL, 0.25 mmol) in THF (5 mL) at 60° C. for 2 h followed by column purification [silica, DCM:ethyl acetate (80:20 to 20:80)].
Reaction SMILES: C([N:4]1[CH2:8][CH:7]2[CH2:9][CH2:10][CH2:11][CH:6]2[C:5]1(C(OCC)=O)[C:12]([O:14]CC)=[O:13])(=O)C.CC(O)=O.[BrH:26]>>[BrH:26].[CH:5]1([C:12]([OH:14])=[O:13])[CH:6]2[CH2:11][CH2:10][CH2:9][CH:7]2[CH2:8][NH:4]1
Reactant: CCOC(=O)C1(C(=O)OCC)C2CCCC2CN1C(C)=O
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)C1NCC2CCCC21
Temperature: 120 °C

Procedure:
A solution of the rac-diethyl 2-acetylhexahydrocyclopenta[c]pyrrole-1,1(2H)-dicarboxylate prepared above in 48% aqueous HBr and AcOH (4:1) was heated at 120° C. for 16 h. The reaction mixture was cooled, concentrated in vacuo and lyophilized to yield the title compound. MS (ESI) 156 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.O.[OH-].[Li+]>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH˜4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC/MS (M+H)+: 446, 1H NMR (DMSO-d6) δ 8.85 (s, 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 5.71 (s, 2H), 5.18 (m, 1H), 3.65 (t, 2H), 3.05 (m, 4H), 0.92 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:46])[NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40]OS(C)(=O)=O)[CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH3:49].C1C[O:53]CC1>>[CH:12]([OH:46])=[O:53].[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH:37]([CH2:40][N:48]([CH3:49])[CH3:47])[CH2:36][CH2:35]5)=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:46])[N:8]([CH3:10])[N:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CNC
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCC(COS(C)(=O)=O)CC4)n3c2)c2ccccc21
Product: CN(C)CC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)CC1
Product: O=CO
Temperature: 65 °C
Yield: 35 %

Procedure:
A solution of Intermediate 14h (57 mg, 0.08 mmol) and dimethylamine (2M in THF, 0.873 mL, 1.75 mmol) in THF (4 mL) was heated at 60° C. for 18 h. A further 1.4 mL of dimethylamine (2M in THF) was added and the reaction mixture was heated at 65° C. for 48 h. The reaction mixture was cooled to RT and the solvent was removed by air, to leave a residue which was purified by MDAP (Method 7), to afford the title compound (18 mg, 35%). LCMS (Method 5): Rt: 3.00 min, m/z 600.4 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.20 (9H, s), 1.32-1.47 (2H, m), 1.64-1.76 (1H, m), 1.76-1.86 (211, m), 1.87-2.12 (4H, m), 2.13-2.21 (9H, m), 2.86-2.99 (2H, m, obscured by water), 3.35-3.48 (2H, m, obscured by water), 3.57 (2H, s, obscured by water), 4.82-4.91 (1H, m), 5.57 (1H, t, J=4.5 Hz), 6.02 (1H, s), 6.91 (1H, d, J=8.8 Hz), 7.18 (1H, dd, J=9.8, 1.9 Hz), 7.26-7.33 (1H, m), 7.34-7.43 (3H, m), 7.62 (1H, d, J=10.0 Hz), 7.65 (1H, d, J=1.8 Hz), 8.19 (1H, s), 8.27 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:57][C:58]([F:69])([F:68])[C:59]1[CH:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)=[C:15]([C:62]4[CH:63]=[CH:64][C:59]([C:58]([F:69])([F:68])[F:57])=[CH:60][CH:61]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C1C(Br)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2ccc(C(F)(F)F)cc2)=C(c2ccc(C(F)(F)F)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 40 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-(trifluoromethyl)phenyl)-1H-inden-1-one obtained in Step 6 of Example 32 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 4-(trifluoromethyl)phenylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (40%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH3:34])[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C)CC1)C3
Yield: 35.4 %

Procedure:
A mixture of Example 64 (100 mg; 0.21 mmol; 1 eq.), paraformaldehyde (56 mg; 0.62 mmol; 3 eq.) and sodium triacetoxyborohydride (88 mg; 0.42 mmol; 2 eq.) in DCE (7 mL) was stirred at reflux for 16 hours. Paraformaldehyde (56 mg; 0.62 mmol; 3 eq.) and sodium triacetoxyborohydride (88 mg; 0.42 mmol; 2 eq.) were added and the reaction mixture was stirred at reflux for one hour. The mixture was partitioned between EA and 1M NaOH and the aqueous layer extracted with EA. The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (2% to 5% MeOH in DCM) followed by recrystallization from ACN afforded the title compound (34 mg, 35%) as a white powder. 1H NMR (DMSO-d6) δ 7.44-7.25 (m, 1H), 7.13 (d, J=11.4 Hz, 1H), 6.86 (td, J=8.3, 2.0 Hz, 1H), 4.92-4.69 (m, 2H), 4.69-4.37 (m, 3H), 2.93-2.70 (m, 3H), 2.61 (s, 1.5H), 2.55 (s, 1.5H), 2.42-2.23 (m, 2H), 2.23 2.04 (m, 2H), 2.04-1.93 (m, 3H), 1.91-1.73 (m, 2H), 1.64-1.47 (m, 2H). HPLC (max plot) 97.4%, Rt 2.81 min. UPLC/MS: (MS+) 458.5 ([M+H]+).
Reaction SMILES: N1C=CC=CC=1C1N=NN(C2C=CC(NC3C4N(C=CN=4)C(C4C=CC(C(N)=O)=CC=4)=CN=3)=CC=2)C=1.[N+:37]([C:40]1[N:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1)([O-])=O.O.O.[Sn](Cl)Cl>CO.Cl>[N:46]1([C:43]2[CH:42]=[CH:41][C:40]([NH2:37])=[N:45][CH:44]=2)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: NC(=O)c1ccc(-c2cnc(Nc3ccc(-n4cc(-c5ccccn5)nn4)cc3)c3nccn23)cc1
Solvent: O
Solvent: CO
Product: Nc1ccc(N2CCOCC2)cn1
Temperature: 0 °C
Yield: 86.4 %

Procedure:
In the same way as described in for Compound 154, step 2 using 4-(6-nitro-pyridin-3-yl)-morpholine (2.39 g, 11.43 mmol), tin(II) chloride dihydrate (12.9 g, 57.17 mmol) in MeOH (40 mL) and conc. HCl (12.4 mL). The reaction mixture is concentrated in vacuo cooled to 0° C. and dissolved in water. The aqueous solution is basified using conc. NaOH and extracted with ethyl acetate (3×). The organic layers are combined, dried over MgSO4, filtered and concentrated to afford the title compound (1.77 g, 87%) which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:4]([CH3:18])[C:3]=1[CH3:19].CC([O-])=[O:22].[Na+]>C(O)(=O)C>[CH3:18][C:4]1[C:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:6][NH:7][C:2](=[O:22])[C:3]=1[CH3:19]
Reactant: Cc1c(Cl)nnc(Cc2ccc(F)c(C#N)c2)c1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Cc2ccc(F)c(C#N)c2)n[nH]c(=O)c1C
Temperature: 25 °C

Procedure:
To a solution of intermediate N2 in acetic acid (0.16 M) was added NaOAc (2 eq.) and the mixture was stirred and heated to reflux for 1 h. The solution was cooled to RT and the solvent was removed under reduced pressure. The residue was suspended in water and triturated until a fine suspension was obtained. The solid material was filtered off, washed with water, dried by air stream and then under high vacuum. MS (ES) C14H12FN3O required: 257. found: 258 (M+H)+.
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH:34]C(OCC)=O)=[C:23]([C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)[CH:24]=3)[CH:16]=[N:15]1)[CH2:10]2)=O)C.[OH-].[K+].O.NN.O>C(O)CO>[CH:11]12[NH:6][CH:7]([CH2:13][CH2:12]1)[CH2:8][CH:9]([N:14]1[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)[C:22]([NH2:34])=[N:21][CH:20]=3)[CH:16]=[N:15]1)[CH2:10]2
Reactant: CCOC(=O)Nc1ncc(-c2cnn(C3CC4CCC(C3)N4C(=O)OCC)c2)cc1-c1nc2ccccc2s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Nc1ncc(-c2cnn(C3CC4CCC(C3)N4)c2)cc1-c1nc2ccccc2s1
Temperature: 200 °C

Procedure:
To a stirring solution of 3-[4-(5-benzothiazol-2-yl-6-ethoxycarbonylaminopyridin-3-yl)-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (7.1 mg, 0.013 mmol, 1 eq) and potassium hydroxide (22.2 mg, 0.396 mmol, 30 eq) in 1,2-ethanediol (3 mL), hydrazine hydrate (7 μL, 0.1 mmol, 10 eq) was added and the solution was stirred at reflux (T=200° C.) for 9 h. The reaction mixture was poured into water and extracted with ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep. TLC [Silicycle, 1000 μm, 20×20 cm plate, developed twice in a 8% 7N NH3(MeOH):CH2Cl2 solvent system.] The desired band was scraped from the plate, the silica gel was completely rinsed of all product, and the filtrate was concentrated in vacuo, giving the title compound as a yellow solid. MS (ES+): m/z=403.17 (40) [MH+]. HPLC: tR=2.37 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)O)[CH:5]=[CH:4][N:3]=1.C(N(S(F)(F)[F:19])CC)C>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([CH:10]2[CH2:12][CH2:11]2)[F:19])[CH:5]=[CH:4][N:3]=1
Reactant: OC(c1ccnc(Cl)n1)C1CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: FC(c1ccnc(Cl)n1)C1CC1
Reaction time: 0.5 h
Yield: 26.4 %

Procedure:
To a solution of (2-chloropyrimidin-4-yl)(cyclopropyl)methanol (75 mg, 0.406 mmol) in dichloromethane (2 mL) at 0° C. was added diethylaminosulfur trifluoride (66 mg, 0.410 mmol) and stirred for 30 min. The solution was concentrated to dryness and purified by flash chromatography on silica gel (0-100% EtOAc/hexanes) to afford 2-chloro-4-(cyclopropyl(fluoro)methyl)pyrimidine (20 mg, 0.107 mmol, 26% yield) as a colorless oil. MS ESI: [M+H]+ m/z 187.1. 1H NMR (500 MHz, CDCl3) δ 8.67 (d, J=5.0, 1H), 7.43 (d, J=5.0, 1H), 4.93 (dd, J=1H), 1.13 (m, 1H), 0.70-0.60 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-])[C:10]=2[CH:11]=1.P(Cl)(Cl)([Cl:15])=O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[N:9]2)=[N:4][CH:3]=1.[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:15])=[CH:7][CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2ncc(Br)cc21
Solvent: ClCCl
Product: Clc1ccc2ncc(Br)cc2n1
Product: Clc1ccnc2cc(Br)cnc12

Procedure:
7.97 g (35.4 mmol, 1 eq) of 3-bromo-1,5-naphthyridine-5-oxide and 9.9 mL (106.2 mmol, 3 eq) of phosphorus oxychloride were introduced in 600 mL of methylene chloride. The mixture was stirred at reflux for 18 h. Methylene chloride was evaporated in part (¾). 1M aqueous NaOH solution was added carefully at 0° C. Aqueous layer was extracted with methylene chloride. Organic layers were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography using methylene chloride as eluent. The solvent was evaporated to dryness to afford 1.97 g of 7-bromo-2-chloro-1,5-naphthyridine (white powder) with 22% yield and 4.16 g of 7-bromo-4-chloro-1,5-naphthyridine (white powder) with 48% yield.