Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([O:54][CH3:55])[C:40]=1[OH:56]>>[NH2:30][C@@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([O:54][CH3:55])[C:40]([OH:56])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(Nc4ccc(N5CCC[C@@H](N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 32.4 %

Procedure:
Following general procedure D, (R)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (30 mg, 32% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.20 (m, 2H), 8.10 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.65 (dd, J=9.1, 2.8 Hz, 1H), 7.05 (d, J=9.1 Hz, 1H), 6.99 (s, 1H), 6.83 (br s, 1H), 4.55-4.49 (d, J=11.6 Hz, 1H), 4.04-3.95 (m, 1H), 3.91 (s, 3H), 3.28-3.18 (m, 3H), 2.87 (br s, 1H), 2.22-2.14 (m, 1H), 1.96-1.87 (m, 1H), 1.76-1.62 (m, 2H), 1.28-1.16 (m, 414).; ESI MS m/z 544 [C30H30ClN5O3+H]+; HPLC>99.0% (AUC), tR=10.74 min.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:46][C:47]1[N:52]=[C:51](O)[CH:50]=[CH:49][CH:48]=1>O.C1COCC1>[Cl:46][C:47]1[N:52]=[C:51]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:50]=[CH:49][CH:48]=1
Reactant: Oc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
Diethyl azodicarboxylate (11 ml, 40% Tol solution) was dropwise added to a THF (30 ml) solution containing tert-butyl 4-hydroxypiperidine-1-carboxylate (4.6 g), triphenylphosphine (6.1 g) and 6-chloro-2-pyridinol (2.0 g) at 0° C., followed by stirring at room temperature for 24 hours. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was washed with an aqueous 1 M sodium hydroxide solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-[(6-chloro-2-pyridinyl)oxy]-1-piperidinecarboxylate (3.8 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([O:33][CH3:34])[C:13]2[CH:18]=[CH:17][N:16]([C@@H:19]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[CH2:20]3)[C:14]=2[N:15]=1>ClCCl>[NH2:9][C:10]1[N:11]=[C:12]([O:33][CH3:34])[C:13]2[CH:18]=[C:17]([Cl:1])[N:16]([C@@H:19]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[CH2:20]3)[C:14]=2[N:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(N)nc2c1ccn2[C@H]1C[C@H](OC(C)=O)[C@@H](COC(C)=O)O1
Solvent: ClCCl
Product: COc1nc(N)nc2c1cc(Cl)n2[C@H]1C[C@H](OC(C)=O)[C@@H](COC(C)=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
36.6 mg (0.27 mmol) of N-chlorosuccinimide are added to a solution of 50 mg (0.14 mmol) of 2-amino-7-(2-deoxy-3,5-di-O-acetyl-β-D-erythropentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine in 3 ml of dichloromethane, and the mixture is stirred at room temperature for 12 h. The solvent is stripped off and the residue is chromatographed on silica gel in CH2Cl2/acetone (9:1). 30 mg (54%) of a colorless foam are obtained from the slowly migrating main zone.
Reaction SMILES: [NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8](Cl)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ncc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: NC(=O)c1c(N)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2c1=O
Temperature: 90 °C
Yield: 24.1 %

Procedure:
A mixture of 184 mg (0.60 mmol) of the product prepared in step 3.3 and 0.266 g (1.49 mmol) of N-(4-aminophenyl)morpholine (Lancaster) in 6 mL of NMP is placed in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM machine, Discover model) and the mixture is heated under pressure at 90°C. for 1 hour at a power of 100 W and then cooled to room temperature. 20 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained by suction and dried in an oven. The crude solid is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (98/2 to 95/5). 0.065 g of the expected product is obtained in the form of a beige-coloured powder. Yield=24%. m.p.=265°C. M+H+=450.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:22][C:23]1[N:24]=[C:25]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:38]([F:41])([F:40])[F:39])=[O:37])=[CH:32][CH:31]=2)[O:26][CH:27]=1.O>CN(C=O)C>[F:41][C:38]([F:39])([F:40])[S:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[O:26][CH:27]=[C:23]([CH2:22][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)(=[O:12])=[O:11])=[CH:19][CH:18]=3)[N:24]=2)=[CH:31][CH:32]=1)=[O:37]
Reactant: O=S(=O)(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CS(=O)(=O)CCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 3.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 134 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfonylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was purified by chromatography on silica gel (eluent: dichloromethane/acetone 20:1) to give 11 mg product.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[Cl:39][C:40]([Cl:45])([Cl:44])[C:41](Cl)=[O:42]>ClCCl>[Cl:39][C:40]([Cl:45])([Cl:44])[C:41]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH3:29])=[CH:21][CH:22]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:42]
Reactant: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)CCCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(c2ccc(C(=O)N3Cc4ccc(C(=O)C(Cl)(Cl)Cl)n4Cc4ccccc43)cc2)CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.7 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[4-(2-methyl-cyclohex-1-en-1-yl)-phenyl]-methanone of Step D (1 g, 2.21 mmol) and N,N-diisopropylethylamine (0.770 mL, 4.42 mmol) were combined in anhydrous dichloromethane (11.1 mL) and trichloroacetyl chloride (0.740 mL, 6.63 mmol) was added dropwise. After stirring at room temperature for four hours, the solvent was removed and the residue dissolved in ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue purified by flash column chromatography. Recrystallization from petroleum ether afforded 1.21 g of the title compound as white crystals, m.p. 171° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.C1(C)C(C)=CC=CC=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][N:20]=1>CCCCCCC>[C:21]([C:18]1[S:17][C:16]([NH:15][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])=[N:20][N:19]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1C
Solvent: CCCCCCC
Product: CC(=O)CC(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A 2-liter reaction flask with appropiate fittings was charged with 33.6 g (0.4 mole) of diketene, 965 ml of xylene and 59.7 g (0.38 mole) of 2-amino-5-tert-butyl-1,3,4-thiadiazole. The stirred mixture was heated to 70° at which time all solids had dissolved. After 1 hour, the solution was cooled and added to 2500 ml of chilled heptane. Product precipitation was judged complete after two hours. The solids were collected on a vacuum filter and air dried. There was obtained 54 g (58.9%) of white product, m.p. 166°-68°. N.M.R. (CDCl3 -dimethyl-d6 sulfoxide) ∂ 1.5 [C(CH3)3 ], 2.0 (CH3, enol), 2.3 (CH3, keto), 3.6 (CH2), 5.4 (CH, enol).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[S:14])[NH:8][C:7]=2[O:6][C:5](=[O:15])[CH:4]=1)[CH3:2].O.[CH3:17]N(C=O)C>>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[NH:10][C:9]([S:14][CH3:17])=[N:8][C:7]=2[O:6][C:5](=[O:15])[CH:4]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc(=O)oc2[nH]c(=S)[nH]c(=O)c12
Solvent: O
Product: CCc1cc(=O)oc2nc(SC)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Mel (2.23 mL, 35.72 mmol) was added to a suspension of 5-ethyl-2-thioxo-2,3-dihydro-1h-pyrano[2,3-d]pyrimidine-4,7-dione (4.0 g, 17.86 mmol) in DMF (40 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water (250 mL) and filtered through a sintered funnel. The solid residue was washed with water (2×50 mL) and dried under vacuum to give 5-ethyl-2-methylsulfanyl-3H-pyrano[2,3-d]pyrimidine-4,7-dione (4.1 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[O:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:7]([C:6]2[O:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:8])=[CH:12][CH:11]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: Cc1ncoc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ncoc1C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-5-oxazolecarbaldehyde (770 mg) in dry tetrahydrofuran (15 ml) was added dropwise to a stirred solution of 4-fluorophenyl magnesium bromide (1M solution in tetrahydrofuran, 7.3 ml) in tetrahydrofuran (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 1 hour the mixture was allowed to warm to room temperature and was then poured into saturated aqueous sodium hydrogen carbonate. Extraction with ethyl acetate followed by flash chromatography gave the title compound. M.p. 102.5°-104° C.
Reaction SMILES: [C:1]1(=[O:20])[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=2)[C:10]([OH:12])=[O:11])[C:5](=[O:19])[CH2:4][CH2:3][CH2:2]1.[OH-:21].[Na+].Cl>[Pd]>[C:10]([C:9]1[CH:8]=[C:7]([CH:15]=[C:14]([NH2:16])[CH:13]=1)[NH:6][C:5](=[O:19])[CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:21])([OH:12])=[O:11]
Reactant: [OH-]
Reactant: O=C(O)c1cc(N2C(=O)CCCC2=O)cc([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Product: Nc1cc(NC(=O)CCCC(=O)O)cc(C(=O)O)c1
Reaction time: 5 h

Procedure:
3-Glutarimido-5-nitrobenzoic acid (55.6 g.) was dissolved in 150 ml. of 10% aqueous sodium hydroxide, the pH adjusted to 8 with 3N hydrochloric acid, 1.0 g. of 10% palladium-on-carbon catalyst added, and the mixture hydrogenated in a Parr apparatus. Reduction was complete in 5 hours. The reaction mixture was filtered and the filtrate containing 3'-carboxy-5'-aminoglutaranilic acid iodinated as described below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=3[O:31][CH3:32])[C:6]=2[CH:33]=1.[CH2:34](I)[CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:34][CH3:35])=[CH:26][C:25]=3[O:31][CH3:32])[C:6]=2[CH:33]=1
Reactant: CCI
Reactant: CCOC(=O)C[C@H]1O[C@H](c2ccc(O)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H]1O[C@H](c2ccc(OCC)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Reaction time: 3 h

Procedure:
A mixture of ethyl trans-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.25 g), ethyl iodide (0.06 ml), potassium carbonate (0.15 g) and N,N-dimethylformamide (200 ml) was stirred for 3 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml). The extract was washed with 1N hydrochloric acid and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give ethyl trans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.24 g) as colorless crystals (mp=164°-166° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[N:6][CH:7]=1.Cl.N[C@H]1CCC[C@@H]1NC(=O)C1C=CC=CC=1N1N=CC=N1.BrC1C=C([C:56]([F:59])([F:58])[F:57])C=CN=1>>[N:23]1[N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([NH:14][C@H:10]2[CH2:11][CH2:12][CH2:13][C@@H:9]2[NH:8][C:5]2[CH:4]=[C:3]([C:56]([F:59])([F:58])[F:57])[CH:2]=[CH:7][N:6]=2)=[O:27])[N:26]=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccnc(Br)c1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(Br)cn1)c1ccccc1-n1nccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cc(C(F)(F)F)ccn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-[(5-bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 118) from N-[(1S,2S)-2-aminocyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 200 mg, 0.65 mmol) and 2-bromo-4-(trifluoromethyl)pyridine (CAS number 175205-81-9; 147 mg, 0.650 mmol) except this was heated to 140° C. for 17 hours to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.CN(C1C=CC=CN=1)C.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:6]([C:12]([O:14][C:30]2[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2ocnc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ocnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methoxybenzoxazole-7-carboxylic acid (0.16 g), dimethylaminopyridine (catalytic) 4-nitrophenol (0.17 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g) in dichloromethane (30 ml) was stirred at room temperature under nitrogen overnight. The mixture was diluted with dichloromethane (20 ml) and washed with water (2×50 ml). The combined organic phases were dried over magnesium sulphate and evaporated in vacuo to give 4-nitrophenyl 4-methoxybenzoxazole-7-carboxylate. 4-Amino-3,5-dichloropyridine (0.15 g) was dissolved in N,N-dimethylformamide (5 ml) at room temperature under nitrogen. Sodium hydride (40 mg; 60% disopersion in oil) was added, and the mixture stirred for 1 h before addition of the 4-nitrophenyl ester (0.26 g) in N,N-dimethylformamide (20 ml). After stirring for 60 h, the N,N-dimethylformamide was evaporated in vacuo, and the residue partitioned between ethyl acetate (40 ml) and water (40 ml). The combined organic phases were washed with water (2×40 ml), dried over magnesium sulphate, evaporated onto silica and purified by flash chromatography eluting with 50% ethyl acetate in hexane) to yield the title compound as a white solid (51 mg).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH2:29])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1.C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[ClH:18].[CH3:19][C:20]1[C:25]([O:26][CH2:27][CH2:28][NH:29][C:2]2[N:9]=[C:8]([NH:10][C:11]3[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=3)[CH:7]=[C:6]([CH3:17])[C:3]=2[C:4]#[N:5])=[CH:24][CH:23]=[C:22]([CH3:30])[N:21]=1
Reactant: Cc1ccc(OCCN)c(C)n1
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(OCCNc2nc(Nc3cc(C)[nH]n3)cc(C)c2C#N)c(C)n1
Temperature: 100 °C
Reaction time: 27 h
Yield: 5.5 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(2,6-dimethylpyridin-3-yloxy)ethylamine hydrochloride (584 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added dropwise to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(2,6-dimethylpyridin-3-yloxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile dihydrochloride (30 mg).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[C:22]([O:30][CH3:31])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([NH:19][CH:2]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9][C:8]=2[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:29]=[CH:28][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(NC(CC(C)C)c2cc(-c3ccccc3)oc2C)ccc1C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-2-methoxybenzoate (1.1 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (5 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.9 g, 46%) as an amorphous compound.
Reaction SMILES: Cl[CH:2]([CH3:5])[C:3]#[N:4].Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>O>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH:2]([CH3:5])[C:3]#[N:4])[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1
Reactant: CC(Cl)C#N
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C#N)N1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 25 parts of 2-chloropropanenitrile, 61 parts of (4-fluorophenyl)(4-piperidinyl)methanone hydrochloride, 63 parts of sodium carbonate and 160 parts of acetonitrile is stirred and refluxed (100° C.) overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (50:49:1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The solid residue is crystallized from 2,2'-oxybispropane. The product is filtered off, and dried yielding 17 parts of 4-(4-fluorobenzoyl)-α-methyl-1-piperidineacetonitrile; mp. 126.7° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([F:42])=[C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24]#[C:25][CH2:26][C@@:27]3([NH:34]C(=O)OC(C)(C)C)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])[N:18]=2)[CH:16]=1)[CH3:9].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[NH2:34][C@:27]1([CH2:26][C:25]#[C:24][C:19]2[N:18]=[C:17]([C:15]3[CH:16]=[C:11]([O:10][CH2:8][CH3:9])[CH:12]=[CH:13][C:14]=3[F:42])[CH:22]=[C:21]([CH3:23])[N:20]=2)[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(NC(=O)OC(C)(C)C)CCN(C)C3=O)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(N)CCN(C)C3=O)n2)c1
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Trifluoroacetic acid (3 mL, 40.39 mmol) was added to a solution of tert-butyl N-[(3R)-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-2-oxo-pyrrolidin-3-yl]carbamate (which may be prepared as described in Description 18) (605 mg, 1.25 mmol) in DCM (15 mL) at 20° C. and the reaction was stirred for 1 hour. Solid K2CO3 was added to quench the TFA present (care: gas evolved) and the resultant solid was filtered off and washed five times with DCM. The solvent was evaporated to give the (3R)-3-amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one (D19) (447 mg, 1.1688 mmol, 93.2% yield) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13].[C:20](Cl)(=[O:22])[CH3:21].[K+].[Br-]>C(O)C>[C:20]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:13])(=[O:22])[CH3:21]
Reactant: Nc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2ccccn2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(pyridine-2-carbonyl)indole (Example 125) and acetyl chloride. m.p.: 211-212° C. (ethanol) 1H-NMR (DMSO-d6) δ: 12.02 (1H, br s), 10.34 (1H, br s), 8.82 (1H, d, J=4.4 Hz), 8.15-8.07 (2H, m), 7.85 (1H, d, J=8.8 Hz), 7.75-7.70 (1H, m), 7.63 (1H, d, J=1.8 Hz), 7.07 (1H, dd, J=1.8, 8.8 Hz), 2.02 (3H, s) IR (KBr) ν: 3450, 1690, 1620, 1580, 1570, 1480, 1350, 1240, 1180, 1160, 1030, 760 cm−1