Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]=[CH2:8])(=[O:3])[CH3:2].[C:9]([NH2:13])(=[O:12])[CH:10]=[CH2:11].ClCCl>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:9]([CH:10]1[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][CH2:8][CH2:11]1)(=[O:12])[NH2:13]
Reactant: C=CC(N)=O
Reactant: C=CC=COC(C)=O
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(=O)OC1C=CCCC1C(N)=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
1-Acetoxy-1,3-butadiene (20.79 g, 0.185 mol) was dissolved in toluene (21 mL). To this was added acrylamide (11.98 g, 0.168 mol) and hydroquinone (0.111 g). The colourless solution was heated at 110° C. for 116 h under argon. More 1-acetoxy-1,3-butadiene (5.67 g, 0.051 mol) was then added, and heating continued for a further 24 h. The solution was cooled then dichloromethane added. This solution was purified by Biotage 75 chromatography twice on silica (2×400 g) to give the title compound as a viscous oil (21.76 g, 71%), which solidified on standing;
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][N:20]=1>>[CH3:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:22]1[CH:21]=[N:20][C:19]([NH2:18])=[N:24][CH:23]=1)=[N:3][C:4]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Nc1ncc(B(O)O)cn1
Product: Cn1cnc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (95 mg) was reacted with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and purified via reverse phase HPLC to give 26.1 mg of 127 as a white solid. MS (Q1) 313.2 (M)+
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].[I:23]I.O>CCCCCC.O1CCCC1>[CH2:6]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[C:17]([F:22])[C:18]([I:23])=[C:19]([F:21])[CH:20]=2)[CH2:13][CH2:14]1)[CH2:7][CH3:8]
Reactant: CCC[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](c2cc(F)c(I)c(F)c2)CC1
Temperature: 25 °C

Procedure:
5.9 ml of a 1.6N butyllithium solution in hexane were added dropwise during 20 min. to a solution of 2.14 g of 1-(trans-4-propylcyclohexyl)-3,5-difluorobenzene in 20 ml of dry detrahydrofuran at -70° C. and the mixture was left to react at -70° C. for 1 hr. Then, a solution of 2.4 g of iodine in 10 ml of dry tetrahydrofuran was added dropwise at -60° C. within 10 min. and the mixture was gradually warmed to room temperature during a further 30 min. The yellow solution obtained was treated with 10 ml of water and then with 10 ml of a 10 percent aqueous sodium bicarbonate solution extracted with ether. The ether solution was washed with sat. sodium chloride solution and several times with water, dried over magnesium sulphate, filtered and concentrated. Chromatography of the residue over 150 g of silica gel with hexane gave 3.27 g of 1-(trans-4-propylcyclohexyl)-3,5-difluoro-4-iodobenzene as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[O:9][C:10]([C:12]1[CH:22]=[C:21]([OH:23])[C:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=2[CH:13]=1)=O>>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:10]([C:12]2[CH:22]=[C:21]([OH:23])[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=2)=[O:9])=[N:3]1
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 3-amino-1-methylpyrazole (201 mg, 2.07 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (45 mg, 0.22 mmol) to give a white solid (28 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1 H) 7.30 (d, J=1.77 Hz, 1 H) 7.05-7.12 (m, 1 H) 7.00 (s, 1 H) 6.80 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.00 (s, 2 H) 1.50 (s, 6 H); LCMS for C15H17N3O3 m/z 288.10 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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(O)C>[CH3:8][C:7]1[C:2]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[CH:3][C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
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: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1ccc([N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To N-(3-iodo-4-methylphenyl)-3-(trifluoromethyl)benzamide (400.0 mg, 0.99 mmol) was added 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (270 mg, 1.1 mmol) followed by toluene (8.2 mL), then ethanol (1.15 mL), and K2CO3 (270 mg, 2.0 mmol in 1.1 mL water). The reaction was degassed with N2, then tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) was added. The reaction was degassed again, and then heated at reflux under N2 atmosphere at 90° C. until LCMS and TLC indicated complete reaction, about 16 hours. The reaction was then cooled to ambient temperature, transferred to a separatory funnel and partitioned between water and EtOAc. The phases were separated and the organic phase was washed with water, then saturated aqueous NaCl, dried (MgSO4) and then evaporated to dryness to leave the crude product, which was purified by column chromatography to give the product (379 mg, 95.79%). 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 2H), 8.12 (s, 1H), 8.07 (d, 1H), 7.82 (m, 2H), 7.5-7.7 (m, 5H), 7.33 (d, 1H), 2.26 (s, 3H). MS (EI) m/z=401 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[N:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cc(O)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(OCc2ccccc2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
To a flame dried flask under N2 was placed 2-chloro-5-hydroxynicotinonitrile (2.0 g, 0.012 mol), DMF (60 mL), NaH (50% oil dispersion, 0.75 g, 0.013 mol) and the mixture cooled to 0°-4° C. A solution of benzyl bromide (1.5 mL, 0.013 mol) in DMF (2 mL) was then added and the solution allowed to stir at room temperature overnight. The mixture was poured into H2O and extracted with Et2O (3X). The organic layer was concentrated to yield 2.0 g (100%) of 5-benzyloxy-2-chloronicotinonitrile. An analytical sample of 5-benzyloxy-3-chloronicotinonitrile was prepared by trituration with C6H14, mp 114°-15° C.; 1H NMR (CDCl3) δ 5.2 (2H, s) 7.4 (5H, s), 7.5 (1H, d, J=3) and 8.35 (1H, d, J=3); IR (nujol) 2220 cm-1 ; MS m/e M+ 244.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]1[CH:26]=[CH:25][C:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)=[O:13])=[N:9][C:7]1=[O:8])C.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:15]([O:14][C:12]([NH:11][C:10]1[CH:25]=[CH:26][N:6]([CH2:5][C:4]([OH:27])=[O:3])[C:7](=[O:8])[N:9]=1)=[O:13])[C:16]1[CH:24]=[CH:23][C:22]2[O:21][CH2:20][O:19][C:18]=2[CH:17]=1
Reactant: CCOC(=O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid ethyl ester (6.40 g, 17 mmol) in tetrahydrofuran (30 mL) and water (60 mL) was added lithium hydroxide monohydrate (1.6 g) at room temperature. After stirring 20 min, the reaction mixture was acidified by adding 1 N HCl (40 mL). The precipitated solid was filtered off, washed with water (20 mL) and ethyl alcohol (20 mL), and dried in vacuo to give the desired product (5.8 g, 98%). 1H-NMR (500 MHz; DMSO-d6) δ 7.94 (d, 1H), 6.93 (d, 1H), 6.90 (s, 1H), 6.82 (s, 2H), 5.93 (s, 2H), 4.99 (s, 2H), 4.43 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH3:27][C@@:28]1([C:34]([OH:36])=[O:35])[CH2:33][O:32][CH2:31][CH2:30][NH:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:29]2[CH2:30][CH2:31][O:32][CH2:33][C@@:28]2([CH3:27])[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: C[C@@]1(C(=O)O)COCCN1
Product: CCOC(=O)C1=C(CN2CCOC[C@@]2(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 59.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.77 g, 1.53 mmol) was reacted with (S)-3-methylmorpholine-3-carboxylic acid (0.22 g, 1.53 mmol) according to the procedure as described in Example 46, Step F to give the title compound as a yellow solid (0.52 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[CH:40][N:39]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Product: Cc1nccc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (137 mg, 0.5 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (187 mg, 0.6 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (30 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([N:38]=[N+]=[N-])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]([N:30]1[CH2:36][C@H:35]([OH:37])[C@@H:34]([NH2:38])[CH2:33][CH2:32][C@H:31]1[CH3:41])=[O:29])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[C@@H]1CC[C@H](N=[N+]=[N-])[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CC[C@H](N)[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
Triphenylphosphine (0.25 g, 0.952 mmol) was added to a solution of (2R,5S,6S)-5-azido-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.193 g, 0.635 mmol) in THF (10 ml) and H2O (0.04 ml), then was heated to 45 degrees C. overnight. The reaction mixture was then diluted with toluene (100 ml×2) and was azeotroped in vacuo by rotary evaporation twice. The resulting oil was dissolved in MeOH and HCl in Et2O and the resulting salt was collected following filtration and was used in the next reaction without further purification (0.27 g, 90%).
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:21][NH2:22]>C(Cl)Cl.O>[CH3:21][NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CNc1c(C(=O)OC)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Methyl 2-fluoro-3-nitrobenzoate (25 g, 0.126 mol) was dissolved in DCM (400 ml) and to this was added Potassium carbonate (34.7 g, 0.25 mol) followed by Methylamine (20.63 ml, 0.5 mol). Reaction was stirred at room temperature under argon. Upon completion reaction was diluted with water and extracted with DCM (3×) then dried over magnesium sulfate. Solvents were removed under reduced pressure to afford methyl 2-(methylamino)-3-nitrobenzoate as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Product: O=C(O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)N3CCC3)nc2)c1

Procedure:
The preparations of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate and 2-(azetidin-1-ylcarbonyl)-5-bromopyridine were described earlier.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=2)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=3)[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1F
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(=O)N(C)C)c2)ccc1=O
Product: CN(C)C(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-dimethyl-benzamide (A-20) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=404.3 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:22])[NH2:21])[CH:17]=[C:16]([Cl:23])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:23])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH2:21])=[O:22]
Reactant: c1cc2[nH]ccc2cn1
Reactant: NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Product: NC(=O)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-carbamoyl benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([CH3:27])[CH:26]=1)[NH:23][C:22](=[O:28])[C:21]2=[O:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][C:25]=3[CH3:27])[C:21](=[O:29])[C:22]2=[O:28])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cc(Cl)cc2c1NC(=O)C2=O
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Product: Cc1cc(Cl)cc2c1N(C(=O)c1cc(Br)nn1-c1ncccc1Cl)C(=O)C2=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
To a suspension of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (see PCT Patent Publication WO 03/015519 for preparation) (97.6% purity, 13.02 g, 42 mmol) and 5-chloro-7-methylindoline-2,3-dione (K. Tsuji et al., Bioorg. Med. Chem. Letters, 2002, 12(17), pp 2427-2430) (7.82 g, 40 mmol) in dry acetonitrile (50 mL) was added 3-picoline (11.9 g, 127 mmol). The mixture was cooled to 0° C., and then methanesulfonyl chloride (6.87 g, 60 mmol) was added dropwise at 0-10° C. After stirring 5 minutes at this temperature, the mixture was warmed to room temperature for 20 hours. The precipitated solids were filtered, washed with acetonitrile (3×5 mL), and dried under nitrogen to afford the title product, a compound of the present invention, as a yellow powder, 14.90 g (77.6% yield), m.p. 173-177° C. (decomp.).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[C:27]([F:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[F:19][C:20]1[C:27]([F:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: O=Cc1ccc(O)c(F)c1F
Product: O=C(C=Cc1ccc(O)c(F)c1F)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(2,3-Difluoro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-difluoro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from acetonitrile.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:26]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([N:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:26]
Reactant: COc1ccc2oc(-c3ccc(N(C)C)cc3)cc(=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)c1ccc(-c2cc(=O)c3cc(O)ccc3o2)cc1

Procedure:
A dichloromethane solution (5 ml) that contained boron tribromide was slowly added to a dichloromethane solution (50 ml) that contained compound 25 (200 mg, 0.68 mmol) while stirring under cooling on ice, and the obtained mixture was then reacted. After completion of the reaction, purified water (100 ml) was added to the reaction solution, and the dichloromethane layer was extracted. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The residue was subjected to silica gel column chromatography using chloroform/methanol (20/1) as an elution solvent, so as to obtain a product of interest, 6-hydroxy-4′-dimethylaminoflavone (compound 27). Yield: 25 mg (yield constant: 13.1%) 1H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.30 (m, 1H), 7.19-7.22 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.73 (s, 1H), 3.03 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]2[CH:53]([NH:54][CH3:55])[CH2:52][N:51]([C:56]([CH:58]3[CH2:63][CH2:62][N:61]([C:64]([C:66]4([CH3:69])[CH2:68][CH2:67]4)=[O:65])[CH2:60][CH2:59]3)=[O:57])[CH2:50]2)[CH:45]=[CH:46][C:47]=1[Cl:48]>CN1C(=O)CCC1.C(OCC)(=O)C>[Cl:41][C:42]1[CH:43]=[C:44]([CH:49]2[CH2:50][N:51]([C:56]([CH:58]3[CH2:59][CH2:60][N:61]([C:64]([C:66]4([CH3:69])[CH2:67][CH2:68]4)=[O:65])[CH2:62][CH2:63]3)=[O:57])[CH2:52][CH:53]2[N:54]([CH3:55])[C:5](=[O:6])[CH2:4][CH2:3][C:2]([F:9])([F:8])[F:1])[CH:45]=[CH:46][C:47]=1[Cl:48]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C(=O)CCC(F)(F)F)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.6 %

Procedure:
To a solution of 4,4,4-trifluorobutyric acid (43 mg, 0.304 mmol) in NMP (1 ml) was added at ambient temperature 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (89 mg, 0.28 mmol) and N,N-diisopropyl ethyl amine (130 μl, 0.760 mmol). After stirring for 15 min a solution {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone (111 mg, 0.253 mmol) in NMP (1 mL) was added and stirred for 18 h at ambient temperature. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with aqueous sodium carbonate (1 M, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:methanol=20:80:0 to 0:85:15) afforded the title compound (109 mg, 77%) as an off-white foam. MS m/e: 562.2 [M]+.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][C@H:7](/[CH:10]=[CH:11]/[C@@H:12]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:13][C@@H:14]([CH3:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C@H:6]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([Se:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:9][CH2:8][C@H:7](/[CH:10]=[CH:11]/[C@@H:12]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH2:13][C@@H:14]([CH3:19])[CH2:15][CH2:16][CH2:17][CH3:18])[C@H:6]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([Se:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34]
Reactant: CCCC[C@H](C)C[C@@H](/C=C/[C@H]1CC[C@H](OC(C)=O)[C@@H]1CCCCCC([Se]c1ccccc1)C(=O)OC)OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCC[C@H](C)C[C@@H](/C=C/[C@H]1CC[C@H](O)[C@@H]1CCCCCC([Se]c1ccccc1)C(=O)OC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a solution of the compound 21 (507 mg) in methanol (7.00 mL) was added potassium carbonate (128 mg) and the solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate and washed with an aqueous saturated ammonium chloride solution and brine. The reaction solution was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane : ethyl acetate=4:1), to give the title compound (370 mg) having the following physical data.
Reaction SMILES: [CH:1]([S:4]([CH2:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:11]=[C:10]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C3C=CC=CC=3)=[CH:23][CH:22]=2)[N:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].C[C@H]1COCCN1C1C=C(C(S(C(C)C)(=O)=O)(C)C)N=C([C:59]2[CH:64]=[CH:63][C:62]([NH:65]C(=O)OC3C=CC=CC=3)=CC=2)N=1>>[CH:62]1([NH:65][C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([C:10]3[N:11]=[C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]4[CH3:20])[CH:13]=[C:8]([CH2:7][S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6])[N:9]=3)=[CH:22][CH:23]=2)[CH2:63][CH2:64][CH2:59]1
Reactant: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CC(C)S(=O)(=O)C(C)(C)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Product: CC(C)S(=O)(=O)Cc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CCC3)cc2)n1

Procedure:
The following compounds were made in an analogous fashion from either phenyl (4-{4-[(isopropylsulfonyl)methyl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}phenyl)carbamate or phenyl N-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(2-propan-2-ylsulfonylpropan-2-yl)pyrimidin-2-yl]phenyl]carbamate and the appropriate amine.