Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[SH:2][C:3]1[N:4]([CH3:13])[C:5](=[O:12])[C:6]2[CH:11]=[N:10][NH:9][C:7]=2[N:8]=1.[Cl:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1>CN(C=O)C.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][S:2][C:3]3[N:4]([CH3:13])[C:5](=[O:12])[C:6]4[CH:11]=[N:10][NH:9][C:7]=4[N:8]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: Cn1c(S)nc2[nH]ncc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)cc3)cc2)nc2[nH]ncc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 6-mercapto-5-methyl-1H-pyrazolo-[3,4-d]pyrimidin-4(5H)-one potassium (1.0 g) in DMF (10 ml) was added 4-(4-chlorobenzoyl)benzyl bromide (1.393 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water and methanol, and recrystallized from methanol to provide the title compound as colorless solid (1.647 g). 1H-NMR (DMSO-d6) δ: 3.53(3H,s), 4.58(2H,s), 7.50(2H,t,J=8.6Hz),,7.65(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.74(2H,d,J=8.6Hz), 7.79(1H,s).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][C:14]=1[CH3:20])[CH3:8].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1Cl)[CH:26]=[O:27]>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:21])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][C:30]2[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][C:23]=2[Cl:22])=[CH:15][C:14]=1[CH3:20])[CH3:8]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with finely powdered K2CO3 (31.8 g, 230 mmol) and anhydrous DMF (104 mL). Next, a solution of compound 10.3 (26.1 g, 115 mmol) and 3,4-dichlorobenzaldehyde (21.0 g, 120 mmol) in anhydrous DMF (52 mL) was added dropwise at 90° C., and the reaction was vigorously stirred at same temperature for 1 h. The reaction mixture was poured into 468 mL of ice-water and extracted with 3×200 mL of AcOEt. The combined organics were sequentially washed with 2×200 mL of water and 100 mL of brine, dried over Na2SO4, and concentrated to a yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexane-20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (34.9 g). 1H NMR (300 MHz) (CDCl3) δ 9.85 (1H, s); 7.81 (1H, d, J=1.5 Hz); 7.50 (1H, dd, J=1.8, 8.1 Hz); 7.37-7.35 (2H, m); 6.80-6.74 (2H, m); 4.71 (2H, s); 4.30 (2H, q, J=7.2 Hz); 2.32 (3H, s); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[CH3:12][C:13]([C:16]([NH2:18])=[NH:17])([CH3:15])[CH3:14].Cl.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[NH:18][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=N)N
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(-c2ccc(Br)cc2)c[nH]1
Temperature: 50 °C
Yield: 80.7 %

Procedure:
A solution of 2,4′-dibromoacetophenone (4.17 g, 15.0 mmol) in N,N-dimethylformamide (60.0 mL) was treated with t-butylcarbamidine hydrochloride (2.05 g, 15.0 mmol) and K2CO3 (4.15 g, 30.0 mmol) and heated to 50° C. for 4 h. Following cooling, the reaction was quenched with water, diluted with brine, and extracted thrice with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification via flash column chromatography (10-40% EtOAc/hexanes) gave the title compound as a light yellow solid (3.38 g; 81%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (d, J=8.1 Hz, 2 H) 7.46 (d, J=8.6 Hz, 2 H) 7.18 (s, 1 H) 1.42 (s, 9 H). MS(ES+) m/e 279/281 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[CH3:44][N:45]1CCOCC1.CN>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:45][CH3:44])=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CN1CCOCC1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2CNC(=O)NC2CC2)cc1=O
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)NC3CC3)cc2=O)c1
Reaction time: 0.33 h

Procedure:
To a cooled (−15° C.) solution of 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate (0.10 mL, 0.75 mmol) in DMF (3.00 mL) was added 4-methylmorpholine (0.08 mL, 0.75 mmol). The solution instantly turned yellow and was dark brown within minutes. After 20 min, methylamine (0.47 mL of 2.0M solution in THF, 0.94 mmol) was added. The reaction was carried out at RT. After 2.5 h, a catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94 mmol) were added. After an additional 2.5 h, the reaction was concentrated to a dark red oil. The crude product was purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (20 mL) and extracted in DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to an off-white solid, dried in vacuo (0.06 g, 19%). 1H NMR (CD3OD/400 MHz) δ 7.85 (m, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.23 (s, 1H), 6.09 (s, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H), 2.49 (m, 1H), 2.11 (s, 3H), 1.91 (s, 3H), 0.71 (m, 2H), 0.48 (m, 2H). ES HRMS m/z 493.2260 (M+H calculated for C27H30N4O4F requires 493.2246).
Reaction SMILES: [C:1]1([S:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([O:30]CC)=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[C:1]1([S:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:28]([OH:30])=[O:29])=[CH:16][N:17]3[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:12][C:11]=2[F:34])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Yield: 74.3 %

Procedure:
In 8.0 ml of dioxane was suspended 800 mg of ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and 4.9 ml of N hydrochloric acid was added thereto, after which the resulting mixture was subjected to reaction under reflux for 4 hours. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene-ethyl acetate (10:1 by volume)] to obtain 560 mg (yield 74.3%) of 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid having a melting point of 252°-258° C.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 13.1 %

Procedure:
A mixture of methyl thiosalicylate (0.56 g, 3.4 mmol), 2-cyano-6-methoxypyridine (0.45 g, 3.4 mmol), triethylamine (0.70 ml, 5.0 mmol) and toluene (50 ml) was refluxed for 48 hrs as described in Example 1. The reaction mixture was concentrated under reduced pressure and recrystallized from ethanol to give the titled compound (0.12 g, 13%) as crystals.
Reaction SMILES: [CH3:1][C:2](=[N:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[N:40][O:41][CH3:42])[C:36](OC)=[O:37])/[C:3](=[N:22]/[O:23][CH2:24][CH3:25])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[CH:6][CH:5]=1.[CH3:43][NH2:44]>C(O)C>[CH3:43][NH:44][C:36](=[O:37])[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][O:27][N:26]=[C:2]([CH3:1])/[C:3](=[N:22]/[O:23][CH2:24][CH3:25])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)=[CH:6][CH:5]=1)=[N:40][O:41][CH3:42]
Reactant: CN
Reactant: CCO/N=C(/C(C)=NOCc1ccccc1C(=NOC)C(=O)OC)c1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Solvent: CCO
Product: CCO/N=C(/C(C)=NOCc1ccccc1C(=NOC)C(=O)NC)c1ccc(OCc2cccc(C(F)(F)F)c2)cc1
Reaction time: 96 h

Procedure:
A mixture of 6.8 g of methyl 2-[[[(1-methyl-2-(4-(3-trifluoromethylphenylmethoxy)-phenyl)-2-E-[ethoxyimino]ethylidene)amino]oxy]methyl]-α-(methoxyimino)-phenylacetate and 4.3 ml of an 8 molar solution of methylamine in ethanol is left to stand at room temperature for 4 days. The mixture is then evaporated in vacuo. The residue is taken up in methyl acetate and the solution is washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from methyl acetate/hexane 1:1. The title compound with a melting point of 130-132° C. is obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]3[O:30][CH2:31][O:32][C:28]=3[CH:27]=2)[S:7](=[O:24])(=[O:23])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][C:42]=1[O:43][CH3:44]>>[O:30]1[C:29]2[CH:33]=[CH:34][C:26]([CH2:25][N:6]3[C:5]([C:3]([OH:2])=[O:4])=[C:10]([C:40]4[CH:39]=[CH:38][C:37]([O:36][CH3:35])=[C:42]([O:43][CH3:44])[CH:41]=4)[C:9]4[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=4[S:7]3(=[O:24])=[O:23])=[CH:27][C:28]=2[O:32][CH2:31]1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Product: COc1ccc(C2=C(C(=O)O)N(Cc3ccc4c(c3)OCO4)S(=O)(=O)c3ccccc32)cc1OC

Procedure:
Prepared according to the method of Example 23, from 2-(benzo[1,3]dioxol-5-ylmethyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester with 3,4-dimethoxyphenyl boronic acid, and saponification according to the method of Example 24; MS (CI) m/e 495, mp 267°-268° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Cl:1][C:2]1[CH:14]=[C:13]([C:15](=[O:21])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccccc1Cl
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)CCC(=O)O)cc1Cl
Temperature: 0 °C
Yield: 75.8 %

Procedure:
12.9 g of ethyl 2-chlorophenoxyacetate (prepared as described in Preparation 1) and 6.00 g of succinic anhydride were dissolved in 70 ml of methylene chloride, and 25.2 g of aluminum trichloride were added thereto in small portions at 0°-5° C., with stirring. The mixture was then stirred at room temperature for 3 hours, poured into ice-water and then extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off in vacuo and the resulting precipitate was recrystallized from a mixture of ethyl acetate and hexane, to give 14.3 g of the title compound melting at 137°-139° C.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([CH:11]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccccc1N
Product: O=C1NC(c2ccccc2)Nc2ccccc21

Procedure:
Anthranilamide was transformed by Method G (using benzaldehyde). M.p. 221-222° C.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=2[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]([NH:30][CH2:31][CH3:32])=[O:29])[C:22]([Cl:38])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Reactant: CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(C)=O)ncc1Cl

Procedure:
Title compound was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-ethyl-3-fluoro-benzamide in an analogous manner to Example 1221d (120° C., 80 min) Isolated 68 mg (34%) as a pale yellow foam. 98% HPLC purity, LCMS 526.16 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 8.11 (s, 1H), 7.68 (s, 1H), 7.48-7.46 (m, 1H), 7.41 (s, 1H), 7.35-7.33 (m, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.69 (bt 1H), 6.38 (bs, 1H), 4.77-4.74 (m, 1H), 4.26-4.20 (m, 1H), 3.69-3.64 (m, 1H), 3.47-3.36 (m, 2H), 2.99-2.93 (m, 1H), 2.66-2.60 (m, 1H), 2.55-2.50 (m, 1H), 1.77 (s, 3H), 1.14 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:8][C:9]([O:11]C)=O)[C:4]([Cl:7])=[CH:5][CH:6]=1.[CH3:13][NH2:14]>>[Cl:1][C:2]1[N:3]([CH2:8][C:9]([NH:14][CH3:13])=[O:11])[C:4]([Cl:7])=[CH:5][CH:6]=1
Reactant: CN
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Product: CNC(=O)Cn1c(Cl)ccc1Cl
Reaction time: 8 h

Procedure:
A mixture of methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate (1.04 g) and methylamine (5 cm3, 33% solution in ethanol) was allowed to stand at room temperature overnight. The solvent was then evaporated and the residue crystallised from isopropanol to give the title compound (0.65 g) m.p. 193°-4° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:35])=[CH:16][C:15]=2[F:36])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH2:33][CH3:34])[C:23]4[N:24]=[C:25]([NH:38][CH3:37])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:35])=[CH:16][C:15]=2[F:36])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc2C)cc2cnc(SC)nc21
Reactant: CN
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc2C)cc2cnc(NC)nc21
Yield: 20 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (0.16 g, 0.315 mmol) and methylamine were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(5-(8-ethyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)urea (62 mg, 20% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.3 (brs, 1H), 8.67 (brs, 1H), 8.61 (brs, 1H), 7.88 (d, J=9 Hz, 1H), 7.80 (brs, 1H), 7.66 (s, 1H), 7.16 (d, J=12 Hz, 1H), 6.00 (s, 1H), 5.73 (s, 1H), 4.34 (br, 2H), 2.89 (d, J=6 Hz, 3H), 2.07 (s, 3H), 1.21 (br, 12H); MS (ESI) m/z: 494.2 (M+H+).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[C:17]([O:28][CH3:29])[CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.C(OCC)(=O)C>[CH3:29][O:28][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[N:11][C:6]3[NH:7][C:8]4[CH:9]=[N:10][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH:14]=2)[CH:20]=[CH:19][C:18]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1cc(-c2cnc3[nH]c4cnc(Br)cc4c3c2)ccc1CN1CCCCC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]c4cnc(-c5cnn(C)c5)cc4c3c2)ccc1CN1CCCCC1
Temperature: 130 °C
Yield: 17.3 %

Procedure:
A degassed mixture of 6-bromo-3-(3-methoxy-4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (350 mg, 0.78 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (242 mg, 1.16 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64 mg, 0.08 mmol) in 2N aqueous sodium carbonate solution (8 mL) and acetonitrile (8 mL) was heated under microwave irradiation at 130° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (75 mL) and washed with water (50 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-25% methanol in DCM) to afford the title compound as an off-white solid (61 mg, 17%). 1H NMR (DMSO-D6, 300 MHz): 8.95-8.92 (m, 2H), 8.85 (d, J=1.0 Hz, 1H), 8.49 (d, J=1.1 Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.44 (d, J=7.7 Hz, 1H), 7.38-7.33 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.48 (s, 2H), 2.44-2.34 (m, 4H), 1.55-1.48 (m, 4H), 1.45-1.37 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12](CC2C=CC=CC=2)[CH2:11][C@H:10]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCC[C@@H]1NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.7 %

Procedure:
cis-4-t-Butyloxycarbonylamino-1-benzyl-3-methylpiperidine(13 g, 0.042 mol) was dissolved in 170 ml methanol and transferred to the Parr pressure reactor after addition of 1.3 g of Pd(OH)2 on carbon. The rqcytoion mixture stirred for 6 hrs at 400 psi pressure at 50° C. Catalyst was removed by filtration and eavaporation of the solvent afforded 8.7 g (95%) of titled compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([CH3:11])=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:11])[CH:6]=4)=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A dry 25 mL flask was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (0.891 g, 5.16 mmol) and thionyl chloride (15 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.0 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.354 g, 3.49 mmol, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])#[CH:2].Cl[C:19]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]3)=[CH:32][CH:31]=2)[N:20]=1.F[B-](F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:4]1[C:5]([C:9]([F:11])([F:10])[F:12])=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:23]1[C:24]([C:25]([F:26])([F:27])[F:28])=[CH:19][N:20]=[C:21]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH:36]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]3)=[CH:32][CH:31]=2)[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1cccc(C(F)(F)F)c1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1c(C#Cc2nc(Nc3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cccc1C(F)(F)F
Temperature: 110 °C

Procedure:
A mixture of methyl 2-(2-ethynyl-6-(trifluoromethyl)phenyl)acetate (A93) (0.113 g, 0.468 mmol), tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K5) (0.222 g, 0.487 mmol), copper(I) iodide (0.005 g, 0.03 mmol), PdCl2(PPh3)2 (0.021 g, 0.030 mmol) and t-Bu3PH.BF4 (0.011 g, 0.038 mmol) in DMF (2.0 mL) was degassed with nitrogen for several minutes before the addition of DIPEA (2.0 mL, 12 mmol) then further degassed with nitrogen for several minutes. The resulting mixture was heated under microwave irradiation 110° C. for 20 minutes and then a further 30 minutes. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound A94 (0.127 g, 41%); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.47 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 4.25 (m, 2H), 4.17 (s, 2H), 3.69 (s, 3H), 2.81 (t, J=12.5 Hz, 2H), 2.65 (m, 1H), 1.83 (d, J=12.6 Hz, 2H), 1.63 (m, 2H), 1.49 (s, 9H). LCMS-A: rt 7.12 min; m/z 661.1 [M−H]+.