Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:15]([CH:18]=3)[C:16]#[N:17])=[CH:9][N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:39].[NH4+:40]>O1CCOCC1>[C:20]([OH:39])(=[O:19])[CH3:25].[C:14]([OH:19])(=[O:39])[CH3:13].[NH2:40][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:15]([CH:18]=3)[C:16]#[N:17])=[CH:9][N:8]([CH:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: [NH4+]
Reactant: [OH-]
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(Cl)ncnc43)CC2)CC1
Solvent: C1COCCO1
Product: CC(=O)O
Product: CN1CCN(C2CCC(n3cc(-c4ccc(Oc5ccccc5)c(C#N)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-5-(4-chloro-7-(4-(4-methylpiperazino)cyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-phenoxybenzonitrile (150 mg) in 1,4-dioxane (25 mL) and 30% aqueous ammonium hydroxide (25 mL) was heated at 120° C. in a sealed tube for 18 hours then cooled and evaporated under reduced pressure. The residue was purified by preparative RP-HPLC to give 5-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-phenoxybenzonitrile bisacetate: 1H NMR (DMSO-d6, 400 MHz) δ 8.14(s, 1H), 7.91(s, 1H), 7.70(d, 1H), 7.55(s, 1H), 7.48(t, 2H), 7.27(t, 1H), 7.20(d, 2H), 7.06(d, 1H), 6.27(bs, 2H), 4.55 (m, 1H), 2.53 m, 4H), 2.36(m, 5H), 2.17 (s, 3H), 2.0(m, 6H), 1.96(s, 6H); MS MH+508.3; RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 7.27 min.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)[C:14](Cl)=O.C(O)C>ClCCl.CN(C)C=O>[CH2:13]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)c(F)c1F
Reaction time: 0.75 h
Yield: 97.3 %

Procedure:
To a solution of 2,3,4-trifluorobenzoic acid (10.85 g, 61.6 mmol) in dichloromethane (100 mL) is added oxalyl chloride (13.5 mL, 154 mmol) and N,N-dimethylformamide (3 drops). After 45 minutes, the reaction mixture is concentrated under vacuum. The resulting residue is dissolved in dichloromethane (100 mL) and to this solution is added ethanol (18 mL, 310 mmol). After 30 minutes, the reaction mixture is diluted with dichloromethane and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound as an oil (12.23 g). 1H NMR (CDCl3): δ 7.93-7.67 (m, 1H), 7.09-6.96 (m, 1H), 4.39 (q, 2H), 1.40 (t, 3H).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)(=[S:3])[NH2:2].Cl[CH2:17][C:18](=O)[CH3:19].C(N(CC)CC)C.CCOC(C)=O>O1CCOCC1>[CH3:19][C:18]1[N:2]=[C:1]([CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)[S:3][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)C1
Reactant: CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1csc(C2CCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a stirred solution of tert-butyl 3-carbamothioylpyrrolidine-1-carboxylate (100 mg, 0.44 mmol) in dry dioxane (1 mL) was added 1-chloropropan-2-one (80 mg, 0.87 mmol) and triethylamine (132 mg, 1.31 mmol). The mixture was stirred at room temperature for over night and refluxed for overnight. The reaction mixture was added EtOAc (10 mL), washed with water (5 mL×3) and brine (5 mL), dried over Na2SO4, filtered, concentrated and purified by preparative TLC (PE:EA=1:1) to give tert-butyl 3-(4-methylthiazol-2-yl)pyrrolidine-1-carboxylate (90 mg, 75%) as a yellow oil.
Reaction SMILES: [CH2:1]1[CH2:17][O:16][C:3]2([CH2:9][O:8][C:7]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])([CH3:10])[CH2:6][CH2:5][CH2:4]2)[O:2]1.N1C=CC=CC=1>C(Cl)Cl.N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6].[O-2].[O-2].[O-2].[Cr+6]>[CH2:17]1[CH2:1][O:2][C:3]2([CH2:9][O:8][C:7]([CH3:10])([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[CH2:6][CH2:5][CH2:4]2)[O:16]1
Reactant: CC1(CCCCO)CCCC2(CO1)OCCO2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CCCC=O)CCCC2(CO1)OCCO2
Yield: 69.5 %

Procedure:
Dry celite (40 g) and 6,6-ethylenedioxy-2-(4'-hydroxybutyl)-2-methyloxepane (4.88 g, 0.0196 mol) in methylene chloride (100 ml) are added to a pyridine-chromium trioxide solution [prepared from pyridine (18.6 g, 0.0284 mol) and chromium trioxide (11.8 g, 0.118 mol)]in dry methylene chloride (500 ml) at 10° C. in a nitrogen atmosphere. After 5 hours the mixture is filtered and the celite is washed with methylene chloride (10×50 ml). The solvent is removed at reduced pressure. The residue is diluted with ether (200 ml), filtered and the ether is removed at reduced pressure. The crude product (4.7 g) is chromatographed on SilicAR CC-7 (100 g) in hexane. Elution with 20% ethyl acetate/hexane gives 6,6-ethylenedioxy-2-methyl-2-(4'-oxobutyl)-oxepane (14) as a clear colorless oil (3,3 g, 70%): ir (neat) 1725 cm-1 (CHO).
Reaction SMILES: [Br-:1].[C:2]1([C:8](=[O:20])[CH2:9][C:10](=[O:19])[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl>[Br:1][C:11]1[C:10](=[O:19])[CH:9]=[C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:20][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccccc1
Reactant: [Br-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(-c2ccccc2)cc(=O)c1Br
Reaction time: 3 h

Procedure:
A solution of bromide (10.25 ml, 0.198 mol) in chloroform (50 ml) was added dropwise over 30 minutes to a stirred solution of ethyl 6-phenyl-2,4,6-trioxohexanoate (52.0 g) in chloroform (400 ml) at -10 to -20° C. The pale solution was stirred for a further 3 hours without cooling, washed with water and evaporated. The residual solid was recrystallised from ethanol-water to give ethyl 3-bromo-4-oxo-6-phenyl-4H-pyran-2-carboxylate (mp 135° C.). This ester was hydrolysed as in Example 33 to give the title product (mp 247° C. with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(O)(C(F)(F)F)=O.[C:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:75])[NH:64][C:65]3[CH:70]=[CH:69][C:68](Br)=[C:67]([O:72][CH2:73][CH3:74])[CH:66]=3)=[CH:59][N:58]=2)[C@H:53]([CH3:76])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].COCCOC.O.C(=O)(O)[O-].[Na+]>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:44]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63](=[O:75])[NH:64][C:65]3[CH:70]=[CH:69][C:68]([C:24]4[CH:25]=[CH:26][C:21]([C:19]5[N:20]=[C:16]([C@@H:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:36])[CH:6]([CH3:7])[CH3:8])[NH:17][CH:18]=5)=[CH:22][CH:23]=4)=[C:67]([O:72][CH2:73][CH3:74])[CH:66]=3)=[CH:59][N:58]=2)[C@H:53]([CH3:76])[CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: CCOc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)nc2)ccc1Br
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: O
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: CCOc1cc(NC(=O)c2ccc(N3CCN(C(=O)OC(C)(C)C)C[C@H]3C)nc2)ccc1-c1ccc(-c2c[nH]c([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of [(S)-2-methyl-1-((S)-2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (253 mg, 0.52 mmol) and the TFA salt of (R)-4-[5-(4-bromo-3-ethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (324 mg, 0.52 mmol; Preparation 21) was dissolved in 1,2-dimethoxyethane (5.32 mL, 51.2 mmol) and water (0.92 mL, 51.2 mmol) and the mixture was sparged under nitrogen. Sodium bicarbonate (161 mg, 1.92 mmol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (89 mg, 0.077 mmol). The reaction mixture was further sparged with nitrogen, sealed under nitrogen and heated at 90° C. overnight. The reaction mixture was extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to produce the title intermediate as a brown oil. (m/z): [M+H]+ calcd for C44H56N8O7 809.43 found 809.6.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[C:10]([O:14][C:15](=[O:19])[CH:16](Br)[CH3:17])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>CN(C=O)C>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:16]([CH3:17])[C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:19])[CH:5]=1
Reactant: Oc1cccnc1
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccnc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 62 %

Procedure:
To a suspension of 1.20 g of sodium hydride (60% oil dispersion; 30.0 mmol) in 10 mL of dry DMF at room temperature were added dropwise 2.85 g of 3-hydroxypyridine (30 mmol) in 10 mL of dry DMF, maintaining the temperature below 40° C., and the mixture was stirred at room temperature for 90 min. Under ice-cooling, 6.28 g of tert-butyl-2-bromopropionate (30 mmol) in 10 mL of dry DMF were slowly added dropwise, maintaining the inner temperature within 5 to 10° C., and then the mixture was warmed to room temperature with stirring for 4 hours. After neutralizing with saturated sodium bicarbonate aq., the mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=2:1) to give 4.15 g of tert-butyl 2-(pyridin-3-yl)oxypropionate (Yield: 62%) as a brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:33][C:34]([CH3:55])([C:45]([O:47]N1C(=O)CCC1=O)=O)[C:35]([O:37]N1C(=O)CCC1=O)=O>>[Cl:30][C:27]1[CH:28]=[C:29]2[C:24](=[C:25]([Cl:31])[CH:26]=1)[CH2:23][N:22]([CH3:32])[CH2:21][CH:20]2[C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:45](=[O:47])[C:34]([CH3:33])([CH3:55])[C:35]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[O:37])(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: CC(C)(C(=O)ON1C(=O)CCC1=O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)C(C)(C)C(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1

Procedure:
Compound 183 was prepared from intermediate 175.1 and bis(2,5-dioxopyrrolidin-1-yl) 2,2-dimethylmalonate (prepared using the methods outlined in example 168) following the procedure outlined in example 175. The crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH)(10%-100%). This resulted in 29.5 mg (5%) of a TFA salt of N1,N3-bis(2-(2-(2-(4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethyl)-2,2-dimethylmalonamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.94-7.92 (m, 4H), 7.57 (m, 2H), 7.51-7.49 (m, 4H), 6.87 (m, 2H), 4.83-4.74 (m, 4H), 4.55-4.50 (m, 2H), 3.92-3.87 (m, 2H), 3.67-3.48 (m, 8H), 3.40-3.38 (m, 4H), 3.18 (s, 6H), 3.14-3.00 (m, 4H), 1.41 (s, 6H). MS (m/z): 551 [½M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([OH:23])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Yield: 89.5 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (6.06 g, 19.2 mmoles) was dissolved in acetone (150 mL), and benzyl bromide (2.60 mL, 21.9 mmoles) and anhydrous potassium carbonate (13.28 g, 96.1 mmoles) were added. The mixture was stirred and heated at reflux for 22 hours. The mixture was concentrated to remove most of the acetone, and ethyl acetate (100 mL) was added. Aqueous hydrochloric acid (1N, 200 mL) was added slowly, swirling frequently to dissolve the solid carbonate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The ethyl acetate solutions were combined and washed with water (100 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to about 50 mL. This solution was heated to boiling, and hexanes (150 mL) were added. The solution was cooled in ice, and crystals slowly formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford 6.97 g (89% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (m.p. 106°-107° C., open capillary, uncorrected).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:39]([CH3:41])([CH3:40])[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=3)[NH:31]2)[CH:27]=[CH:28][CH:29]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:23][C:24]1[CH:25]=[C:26]([CH:30]2[C:39]([CH3:40])([CH3:41])[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([C:42]([OH:44])=[O:43])[CH:36]=3)[NH:31]2)[CH:27]=[CH:28][CH:29]=1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)c2cccc(F)c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
A solution of 3-fluoro-benzoic acid (119 mg, 0.85 mmol) and 1,1′-carbonyldiimidazole (179 mg, 1.1 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.68 mmol) in N,N-dimethylformamide (1.5 mL) was added and the mixture was allowed to stir at 50° C. for 3 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3-fluoro-benzoylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (40 mg, 14%) as a white solid: LC/MS m/e calcd for C25H23FN2O3 (M+H)+: 419.47, observed: 419.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:15]([N:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:42](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:14]([C:15](=[O:16])[N:17]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:42])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:13]=1)[C:35]1[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)c2ccccc2F)c1)c1ccncc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino)-butyric acid (0.100 g), TBTU (0.112 g) and HOBt (0.047 g) in DMF (2 ml) was added DIPEA (0.060 ml) followed by a 0.5M solution of ammonia in 1,4-dioxane (0.70 ml) after 10 min. The reaction mixture was stirred at room temperature for 70 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.100 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10].[NH3:12]>O1CCOCC1>[NH2:12][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([NH2:11])=[O:10]
Reactant: N
Reactant: NC(=O)c1cnc(Cl)cc1Cl
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Cl)cc1N

Procedure:
To a well stirred solution of 4,6-dichloropyridine-3-carboxamide (11.0 g, 57.59 mmol) in 1,4-dioxane (20 mL) in steel bomb was added the liquid ammonia (50 mL, 57.59 mmol). The steel bomb was closed and heated the reaction to 100° C. for 9 h. The progress of the displacement reaction was monitored by TLC and LCMS. After completion the solid formed was filtered. The filtrate was also concentrated as it also contains 50% product. The combined solids were dried under vacuum to afford 4-amino-6-chloro-pyridine-3-carboxamide (2) as a light brown solid. Yield: 10.6 g, crude, 47%; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.97 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 6.65 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9]C[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1>>[BrH:9].[CH3:7][C:5]1[N:6]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:2](=[NH:1])[S:3][C:4]=1[CH3:8]
Reactant: BrCCC1CCCCO1
Reactant: Cc1nc(N)sc1C
Product: Br
Product: Cc1sc(=N)n(CC2CCCCO2)c1C

Procedure:
A mixture of 2-amino-4,5-dimethylthiazole and 2-(bromoethyl)tetrahydro-2H-pyran were processed as described in Example 2A to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.31 (m, 1H), 1.36-1.52 (m, 3H), 1.64-1.85 (m, 2H), 2.18 (d, J=4 Hz, 6H), 3.19-3.33 (m, 1H), 3.49-3.63 (m, 1H), 3.77-3.89 (m, 1H), 3.94-4.02 (m, 2H), 9.34 (s, 2H); MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:15]([C:19]1[Se:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([NH2:27])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)(C)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:27][C:21]1[CH:20]=[C:19]([C:15]([CH3:18])([CH3:16])[CH3:17])[Se:23][C:22]=1[C:24]([NH2:26])=[O:25])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Solvent: CC(C)O
Product: CC(C)(C)c1cc(Nc2ncnc3ccc([N+](=O)[O-])cc23)c(C(N)=O)[se]1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 4-chloro-6-nitroquinazoline (1.1 g, 5.2 mmol) in isopropanol (10 mL) was added 5-tert-butyl-3-amino-selenophene-2-carboxamide (2.58 g, 10.50 mmol) at rt and the mixture was stirred for 30 min. The mixture was poured into ice cold water and stirred for 15 min The precipitated solid was filtered, washed with water and dried to give the product as a pale yellow color solid (2.1 g, 95%), mp 280-282° C. 1H NMR (400 MHz, DMSO-d6): δ 13.23 (1H, br s), 9.05 (1H, br s), 8.85 (1H, s), 8.56-8.60 (2H, m), 7.98 (1H, d, J=9.2 Hz), 7.80 (2H, br s), 1.43 (9H, s); LC-MS (negative ion mode): m/z 416, 418 (M−H)−.
Reaction SMILES: I[C:2]1[C:7]([CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:18])[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[O:32]1[C:43]2[C:44]3[C:39]([C:40](B(O)O)=[CH:41][CH:42]=2)=[N:38][CH:37]=[CH:36][C:35]=3[CH2:34][CH2:33]1.C(OCC)(=O)C>COCCOC.O.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>[CH3:18][C:6]1[N:5]=[C:4]2[S:19][C:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=3[C:3]2=[C:2]([C:40]2[C:39]3[C:44]4=[C:35]([CH2:34][CH2:33][O:32][C:43]4=[CH:42][CH:41]=2)[CH:36]=[CH:37][N:38]=3)[C:7]=1[CH:8]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc2c4c(ccnc14)CCO2)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
To a solution of methyl 2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate (0.065 g; 0.136 mmol) in a mixture of DME-water (3:1) (0.480 mL) were added potassium carbonate (0.057 g; 0.409 mmol), tetrakis(triphenylphosphine)palladium(0) (0.016 g; 0.014 mmol) and 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (0.044 g; 0.205 mmol). The solution was stirred for 30 min at 140° C. under a microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-80%) in heptane furnished 0.048 g (68%) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH3:7])[CH:5]=[N:4][N:3]=1.[CH2:8]=[O:9]>>[CH3:7][N:6]1[C:2]([CH3:1])=[N:3][N:4]=[C:5]1[CH2:8][OH:9]
Reactant: Cc1nncn1C
Reactant: C=O
Product: Cc1nnc(CO)n1C
Temperature: 90 °C
Yield: 82 %

Procedure:
A mixture of 3,4-dimethyl-4H-1,2,4-triazole (2.3 g, 23.7 mmol) and formalin (5 mL) was heated to 90° C. overnight. The mixture was concentrated to give crude product. The crude product was purified by silica gel chromatography (dichloromethane/methanol=200:1 to 15:1) to give the title compound (2.48 g, yield 82%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.31 (s, 3H), 3.52 (s, 3H), 4.52-4.54 (d, J=5.2 Hz, 2H), 5.49-5.51 (t, J=5.2 Hz, 1H). LC-MS (ESI) m/z: 128 (M+1)+.