Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:47][C:48]([F:60])([F:59])[O:49][C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:53]3[CH:52]=[CH:51][C:50]([O:49][C:48]([F:47])([F:59])[F:60])=[CH:55][CH:54]=3)=[CH:2][CH:38]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 86.9 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethoxyphenylboronic acid (0.145 mg, 0.69 mmol) by following general procedure D yielding the title compound (101 mg, 85%) as a white solid:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:10]([OH:16])[C:11](=[NH:15])OCC)[CH:6]=[CH:7][C:8]=1[F:9].[NH2:17][CH2:18][CH2:19][CH2:20]N>C(O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:10]([CH:11]2[NH:15][CH2:20][CH:19]=[CH:18][NH:17]2)[OH:16])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCOC(=N)C(O)c1ccc(F)c(Br)c1
Reactant: NCCCN
Agent: Cl
Solvent: CCO
Product: OC(c1ccc(F)c(Br)c1)C1NC=CCN1
Temperature: 120 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of ethyl 2-(3-bromo-4-fluorophenyl)-2-hydroxyethanimidoate Hydrochloride (39.8 g, 127 mmol) and 1,3-diaminopropane (9.43 g, 127 mmol) in ethanol is heated at 120° C. in a sealed tube overnight, cooled to room temperature, concentrated to remove the solvent, diluted with water, stirred vigorously for 1 h and filtered. The filtrate is cooled with an ice bath, made strongly basic with 1 N NaOH, cooled for 1 h in an ice bath and filtered. The filtercake is dried to afford th title compound as a white solid 23.4 g (64% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 7.59 (m, 1H), 7.30 (m, 1H), 7.10 (t, J=8.4 Hz, 1H), 4.79 (s, 1H), 3.35 (m, 4H), 1.76 (m, 2H); ESI MS m/z 287 [C11H12BrFN2O+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[N+:12]([O-:14])=[O:13]>C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Br:1][C:9]1[CH:8]=[CH:7][C:6]([O:10][CH3:11])=[C:5]([N+:12]([O-:14])=[O:13])[C:4]=1[F:3]
Reactant: COc1cccc(F)c1[N+](=O)[O-]
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Br)c(F)c1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 17 h
Yield: 99.3 %

Procedure:
Bromine (1.55 mL, 30.1 mmol) was added dropwise to a solution of 1-fluoro-3-methoxy-2-nitrobenzene (1.29 g, 7.53 mmol) in acetic acid (15.1 mL). The reaction mixture was warmed to 55° C. and stirred at 55° C. for 17 h, after which time the reaction mixture was concentrated in vacuo to give a crude solid. The crude solid was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. Layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the desired product (1.87 g, 99%) as a yellow solid that was used in further step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[NH:24][C:25](=[O:41])[C:26]1[CH:31]=[C:30]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]2)[CH:29]=[CH:28][C:27]=1[NH2:40].[CH:42](OCC)(OCC)OCC>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH:13]=[C:12]([F:22])[CH:11]=2)=[CH:4][C:3]=1[N:24]1[C:25](=[O:41])[C:26]2[C:27](=[CH:28][CH:29]=[C:30]([N:32]3[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]3)[CH:31]=2)[N:40]=[CH:42]1
Reactant: CN1CCCN(c2ccc(N)c(C(=O)Nc3cc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)ccc3F)c2)CC1
Reactant: CCOC(OCC)OCC
Product: CN1CCCN(c2ccc3ncn(-c4cc(NC(=O)c5cc(F)cc(N6CCOCC6)c5)ccc4F)c(=O)c3c2)CC1
Yield: 63 %

Procedure:
Using an analogous procedure to that described in Example 18, N-[2-fluoro-5-(3-fluoro-5-morpholinobenzamido)phenyl]-2-amino-5-(4-methylhomopiperazin-1-yl)benzamide was reacted with triethyl orthoformate to give the title compound in 63% yield; NMR Spectrum: (DMSOd6) 1.92 (m, 2H), 2.25 (s, 3H), 2.46 (m, 2H), 2.64 (m, 2H), 3.21 (t, 4H), 3.53 (t, 2H), 3.6 (m, 2H), 3.72 (t, 4H), 6.99 (d, 1H), 7.12 (d, 1H), 7.23 (m, 1H), 7.3 (s, 1H), 7.36 (m, 1H), 7.48 (t, 1H), 7.58 (d, 1H), 7.87 (m, 1H), 7.96 (m, 1H), 8.06 (s, 1H), 10.43 (s, 1H); Mass Spectrum: M+H+575.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)N1CCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 38.8 mg (0.54 mmol) of pyrrolidine. Yield: 17 mg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[CH:12][N:11]=2)[CH:6]=1
Reactant: Clc1nccc(N2CCOCC2)n1
Reactant: Brc1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(-c2nccc(N3CCOCC3)n2)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a cooled (0° C.) solution of 4-bromo-1H-pyrazole (0.74 g, 5.0 mmol) in anhydrous DMF (7 ml) was added NaH (60% dispersion in mineral oil, 0.22 g, 5.5 mmol) in a portionwise fashion over 10 minutes. The mixture was stirred like this for 30 minutes before the addition of 4-(2-chloro-pyrimidin-4-yl)-morpholine (21)(1.0 g, 5.00 mmol). The reaction was then heated under the influence of microwave radiation (120° C., 14 minutes, fixed hold time, high absorption setting). The reaction was then cooled to room temperature and water added (14 ml) which caused a precipitate to form. The solid was collected by filtration, washed with water and dried in a desiccator to give the title compound (1.44 g, 93%) in sufficiently pure form to be used without any further purification. m/z (LC-MS, ESP): 310 [M+H]+, R/T=3.08 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[C:12]([CH:15]=O)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[C:12]([CH:15]=[N:25][OH:26])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2C=O)n1
Reactant: NO
Agent: Cl
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2C=NO)n1

Procedure:
Was prepared according to example 20 from 5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-pyrazine-2-carbaldehyde and hydroxylamine, hydrochloride.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22](N3CCCCC3)[CH2:23][Br:24])[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:11](=[O:31])[CH:10]2[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C[OH:45]>>[CH:1]1([CH2:4][O:5][C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22]([OH:45])[CH2:23][Br:24])[C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:20])[Cl:21])=[O:15])[C:11](=[O:31])[CH:10]2[NH:32][C:33](=[O:42])[CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(CBr)N2CCCCC2)C1SC(=O)OCC1CC1
Agent: Cl
Product: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(O)CBr)C1SC(=O)OCC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-[2-bromo-1-(piperidin-1-yl)ethylidene]acetate (573 mg) in methanol (30 ml) is added 10% hydrochloric acid (7 ml), and the mixture is stirred at room temperature or at 40° to 45° C. After 30 minutes, the reaction mixture is poured into ice water, and is extracted with benzene. The extract solution is washed with water, dried, and evaporated to give 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl]-α-(2-bromo-1-hydroxyethylidene)-acetate (434 mg). Yield: 83.5%. IR: νmaxCHCl3 3450, 1790, 1720, 1720 (sh), 1700 cm-1. NMR: δCDCl3 0.1-1.4m7H, 3.98d(7 Hz)2H, 4.27d(5 Hz)2H, 4.57s2H, 4.82d(3 Hz)2H, 5.27d(6;8 Hz)1H, 5.93d(5 Hz)1H, 6.8-7.5m6H, 11.67bra1H.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][NH2:8])=[CH:2]1.[CH3:9][O:10][CH2:11][C:12](Cl)=[O:13].C(N(CC)CC)C.Cl>C1COCC1>[CH3:9][O:10][CH2:11][C:12]([NH:8][CH2:7][CH2:6][C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:13]
Reactant: COCC(=O)Cl
Reactant: NCCc1ccsc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCCc1ccsc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10.0 g (78.6 mmol) 2-thiophen-3-yl-ethylamine are dissolved in 120 ml THF and at −10° C. combined successively with 7.9 ml (86.5 mmol) methoxyacetic acid chloride and a solution of 21.9 ml (157.2 mmol) triethylamine in 30 ml THF. The mixture is heated to RT and stirred for one hour. Then it is acidified with 2N hydrochloric acid and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:12][CH2:11][C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[CH3:20])[CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: Cc1cc(Br)ccc1[C@@H](CO)COCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Br)ccc1[C@H](COCc1ccccc1)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To 16F (0.6 g, 1.790 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.299 mL, 2.148 mmol) and MsCl (0.167 mL, 2.148 mmol). The reaction was stirred at rt for 2 h. The solvent was removed and residue was redissolved in EtOAc. The solution was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (0-40% ETOAc/hexanes) to give 24A (0.74 g, 1.790 mmol, 100% yield) as an oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.28-7.40 (m, 7H) 7.13 (d, J=8.34 Hz, 1H) 4.39-4.59 (m, 4H) 3.69 (d, J=5.81 Hz, 2H) 3.52-3.62 (m, 1H) 2.85 (s, 3H) 2.33 (s, 3H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36]>>[CH2:1]([C@H:8]([C:9]([NH:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36])=[O:11])[CH2:12][CH2:13][C@H:14]([CH2:18][CH3:19])[C:15]([NH:20][C@H:21]1[CH2:27][CH2:26][S:25][C@H:24]2[CH2:28][CH2:29][CH2:30][C@@H:31]([C:32]([O:34][CH3:35])=[O:33])[N:23]2[C:22]1=[O:36])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)O)C(=O)O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N21
Product: CC[C@@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O)C(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)OC)N2C1=O

Procedure:
Methyl (4S,7S,10aS)-4-(((2S,5R)-5-benzyl-2-ethyl-6-(((4S,7S,10aS)-7-(methoxycarbonyl)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepin-4-yl)amino)-6-oxohexanoyl)amino)-5-oxooctahydro-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure F using Intermediate 82 (33 mg, 0.13 mmol) and (4S,7S,10aS)-methyl 4-amino-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (121 mg, 0.312 mmol) to give a white solid (25 mg, 27% yield). Anal. Calcd. for C37H52N4O8S2 m/z 744.3. found: 745.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.47 (m, 1H), 7.23-7.13 (m, 5H), 5.40-5.30 (m, 2H), 5.19-5.12 (m, 3H), 4.99 (m, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.28-3.12 (m, 2H), 2.92-2.71 (m, 14H), 2.41 (m, 3H), 2.24 (m, 1H), 2.05-1.98 (m, 6H), 1.80-1.44 (m, 14H), 0.86 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(OC(=O)[N:7]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]1)[C:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1)=[O:9])(C)(C)C.[H-].[Na+].IC>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][N:22]([NH:7][C:8]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][CH:11]=2)=[O:9])[CH2:27][CH2:26]1
Reactant: COCCN1CCN(N(C(=O)OC(C)(C)C)C(=O)c2cnc(-c3ccccc3)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCCN1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 44.6 %

Procedure:
A solution of [4-(2-methoxy-ethyl)-piperazin-1-yl]-(2-phenyl-pyrimidine-5-carbonyl)-carbamic acid tert-butyl ester (0.21 mmol), NaH (60%, 0.66 mmol) and iodomethane (0.63 mmol) in DMF (8 mL) is stirred under N2 at rt overnight. The reaction mixture is quenched with water, and extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 0-2% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid [4-(2-methoxy-ethyl)-piperazin-1-yl]-amide (32 mg, 44%) as a solid. MS: 342 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])=[CH:18][CH:19]=2)[N:14]=1.C(O)C>O>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: Nc1ccc2ccc(Oc3ccccc3Cl)nc2n1
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)Nc2ccc3ccc(Oc4ccccc4Cl)nc3n2)cc1
Temperature: 4 °C
Yield: 64.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-methoxybenzoic acid (16.4 g), N,N'-carbonyldiimidazole (17.5 g) and 2-amino-7-(2-chlorophenoxy)-1,8-naphthyridine (18.5 g). The product produced by precipitation in water (28 g; m.p. approximately 80° C.) is dissolved in boiling ethanol (800 cc). After 15 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with ethanol (2×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-[7-(2-chlorophenoxy)-1.8-naphthyridin-2-yl]-4-methoxybenzamide (17.8 g) is produced, m.p 190° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH2:17][CH2:18][OH:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.C1COCC1.[C].[Pd]>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: OCCC=Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OCCCCc1ccc(O)cc1
Yield: 99 %

Procedure:
4-(4-benzyloxyphenyl)-3-buten-1-ol (1.70 g) was dissolved in a mixture of methanol-THF (1:1, 20 ml); 10% palladium carbon (0.17 g) was added, followed by vigorous stirring in a hydrogen atmosphere for 1.5 hours. The catalyst was filtered off; the filtrate was concentrated under reduced pressure to yield the titled compound (1.1 g) as a colorless crystalline powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.22 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.154 g, 69%). MS (ISP) 446.3 [(M+H)+]; mp 194° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34](O)=[O:35])=[C:27]2[CH:26]=1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([NH2:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[C@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]1[CH:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34]([NH:47][S:44]([C:41]3[CH:40]=[CH:39][C:38]([F:37])=[CH:43][CH:42]=3)(=[O:46])=[O:45])=[O:35])=[C:27]2[CH:26]=1
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: NS(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(F)cc1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 20 h
Yield: 6.4 %

Procedure:
EDCI (111 mg, 0.5 mmol) was added to a solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.29 mmol) in DCM (4 mL) followed by DMAP (36 mg, 0.29 mmol) and 4-fluorobenzenesulfonamide (56 mg, 0.31 mmol) and stirring was continued at 20-35° C. for 20 h. Reaction mixture was quenched with water, extracted into EtOAc, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude. The crude compound was purified by Preparative HPLC [Column: 21.2×150×5 um, Zorbax, Eclipse, C-18, Mobile phase-A: Water, B:ACN, Gradient (Time/% B): 0/30, 2/40, 10/80 and Flow rate: 20 mL/min] to afford 9.3 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:27]=[CH:26][C:25]([CH2:28][N:36]4[CH2:41][CH2:40][CH:39]([C:42]([OH:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]4)=[CH:24][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a 0° C. cooled solution of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (1 g, 2.350 mmol) in DCM (25 mL) was added thionyl chloride (0.858 mL, 11.75 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. After 30 minutes, the solvent was removed at reduced pressure, and the residue was suspended in ACN (5 mL) and re-concentrated to remove residual thionyl chloride. The residue was resuspended in ACN (15 mL), cooled to 0° C., and 2-(piperidin-4-yl)propan-2-ol (1.010 g, 7.05 mmol) and TEA (0.655 mL, 4.70 mmol) were added. The reaction was stirred overnight at RT. After 16 hours, the reaction mixture was concentrated and partitioned between EtOAc and water. The organic layer was concentrated and the residual product was purified by column chromatography, eluting with 0-100% (90:9:1 DCM/MeOH/NH4OH)/DCM to provide cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate as a white powder (1.05 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (s, 6H), 1.09-1.35 (m, 3H), 1.56-1.91 (m, 8H), 2.21-2.29 (m, 2H), 2.53-2.64 (m, 2H), 2.77-2.95 (m, 3H), 3.50 (s, 2H), 3.77 (s, 3H), 3.99 (s, 1H), 4.74 (br. s., 1H), 7.14 (d, J=6.9 Hz, 1H), 7.26 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.37-7.58 (m, 2H), 8.26 (dd, J=8.7, 5.9 Hz, 2H), 12.77 (s, 1H). MS, m/z (C31H39FN4O4): calcd, 550.3. found, 551.1 [M+H].
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=2)=[C:4]([O:16][CH3:17])[CH:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=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.COCCOC.O>[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:3][C:4]=2[O:16][CH3:17])[N:8]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1cc(Cl)ccc1Oc1cccc(F)n1
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: COCCOC
Solvent: O
Product: COc1cc(-c2ccc(C)cc2)ccc1Oc1cccc(F)n1
Temperature: 105 °C
Reaction time: 48 h

Procedure:
To a solution of 2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine (0.53 mmol; 135 mg) and 4-methylphenylboronic acid (0.94 mmol; 127 mg) in a degased DME/water mixture (1.5/0.5 mL), under argon were added K2CO3 (2.0 mmol; 276 mg), then tetrakis(triphenylphosphine)palladium (0.07 mmol; 47 mg). The reaction was stirred at 105° C. for 48 hr. After concentration, the residue was purified by flash chromatography (gradient cyclohexane/dichloromethane) to yield the desired product along with remaining starting material (160 mg; 0.53 mmol; 100% max).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1.CN(C)C=[O:20]>C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([OH:20])[CH2:14][CH2:13][N:12]([CH3:15])[C:11]2=[O:16])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: CN1CCC(c2ccc(Br)cn2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CN1CCC(O)(c2ccc(Br)cn2)C1=O
Reaction time: 1.5 h

Procedure:
Sodium hydride (55% in mineral oil, 0.13 g) was added to a solution of 3-(5-bromo-pyridin-2-yl)-1-methyl-pyrrolidin-2-one (0.69 g) in N,N-dimethylformamide (10 mL) at room temperature. The resulting mixture was stirred in the presence of air for 1.5 h and then diluted with ethyl acetate. The precipitate formed thereafter was separated by filtration, washed with ether, and dried. The title compound was obtained as a colorless solid. Yield: 0.71 g (93% of theory); LC (method 1): tR=1.38 min; Mass spectrum (ESI+): m/z=271/273 (Br) [M+H]+.