Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:9][O:10][C:11]1[C:12]([Cl:29])=[CH:13][C:14]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([F:28])([F:27])[F:26])[O:17][C:15]=2[CH:16]=1)(C)(C)C.Cl.C(OCC)C>C(Cl)Cl>[Cl:29][C:12]1[C:11]([O:10][CH2:9][C@@H:8]([NH2:7])[CH2:30][CH:31]([CH3:33])[CH3:32])=[CH:16][C:15]2[O:17][CH:18]([C:25]([F:27])([F:28])[F:26])[C:19]3[C:24]([C:14]=2[CH:13]=1)=[CH:23][CH:22]=[N:21][CH:20]=3
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1cc2c(cc1Cl)-c1ccncc1C(C(F)(F)F)O2
Reaction time: 14 h
Yield: 23 %

Procedure:
To a stirred solution of tert-butyl((2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (50 mg, 0.100 mmol) in DCM (10 mL) was added 1M HCl in diethyl ether (0.100 mmol) at room temperature and the solution stirred for 14 h. The solvent was removed under reduced pressure to afford a residue which was purified by preparative HPLC using 0.1% TFA in methanol. The purification afforded (2S)-1-((9-chloro-5-(trifluoromethyl)-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (10 mg, 0.023 mmol, 23% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J=5.2 Hz, 1 H), 8.57 (s, 1 H), 8.32 (s, 1 H), 7.98 (d, J=5.2 Hz, 1 H), 6.97 (s, 1 H), 6.45 (m, 1 H), 3.9 (m, 1 H), 3.87 (m, 1 H), 3.09 (m, 1 H), 1.83 (m, 1 H), 1.33 (m, 2 H), 1.31-1.26 (m, 6 H); LCMS (ESI) m/e 401.2 [(M+H)+, calcd for C19H21ClF3N2O2 401.1]; LC/MS retention time (Method C): tR=1.69 min; HPLC retention time (method A): tR=5.80 min, 5.87 min (diastereomeric mixture); HPLC retention time (method B): tR=6.41 min, 6.45 min (diastereomeric mixture).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37]([N:45]1[C@H:49]([C:50](O)=[O:51])[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[C:37]([N:45]1[C@H:49]([C:50](=[O:51])[NH:10][C@H:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=2)[CH2:48][S@@:47](=[O:53])[CH2:46]1)(=[O:44])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[C@@H](N)c1ccc(O)cc1
Reactant: O=C(O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)[C@@H]1C[S@@](=O)CN1C(=O)c1ccccc1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
9.47 g (69.11 mmole) of (R)-α-methyl-p-hydroxybenzylamine (prepared as described in Preparation 13), 10.58 g (69.11 mmole) of N-hydroxybenzotriazole monohydrate and 14.26 g (69.11 mmole) of dicyclohexylcarbodiimide were added in that order to a solution of 17.50 g (69.11 mmole) of (1R,4R)-3-benzoyl-1-oxo-thiazolidine-4-carboxylic acid (prepared as described in Preparation 10) in 100 ml of dimethylformamide cooled at 5° C., and the mixture was stirred at a temperature between 3° and 6° C. for 30 minutes and then at room temperature for a further 4 hours. At the end of this time, the reaction mixture was filtered and the insolubles were washed with 100 ml of hot dimethylformamide. The filtrate and the washings were combined and concentrated by evaporation under reduced pressure to leave crystals. These crystals were recrystallized from methanol to give 19.21 g (74.6%) of the title compound in the form of colorless needles melting at 233°-234° C.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[C:6]=2[CH2:5][CH2:4][CH2:3]1.[O:14]=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[N:16]1[CH2:25][CH2:26][CH2:27][CH:28]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:13][O:12][C:7]1[C:6]2[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][CH2:28][CH2:27][CH2:26][CH2:25][N:16]3[C:17](=[O:24])[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:15]3=[O:14])[C:11]=2[N:10]=[CH:9][CH:8]=1
Reactant: COc1ccnc2c1CCCC2N
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc2c1CCCC2NCCCCN1C(=O)c2ccccc2C1=O
Yield: 54.4 %

Procedure:
Using General Procedure B: Reaction of 8-amino-4-methoxy-5,6,7,8-tetrahydroquinoline (0.297 g, 1.67 mmol) and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (0.371, 1.71 mmol) with NaBH(OAc)3 (0.493 g, 2.33 mmol) in CH2Cl2 (8 mL) for 60 minutes followed by purification of the crude material by column chromatography on silica gel (20:1 CH2Cl2—CH3OH) provided 0.345 g (54%) of 2-[4-(4-Methoxy-5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione as an off-white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(CO)cc1OC1CCCC1
Yield: 97.9 %

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (38 grams, 0.17 mol) in 40 milliliters of ethanol and sodium borohydride (1.63 grams,0.043 mol) was stirred for 2 hours at room temperature until complete by TLC. The reaction was diluted with water and extracted with ethyl acetate. Evaporation of the ethyl acetate afforded 3-cyclopentyloxy-4-methoxybenzyl alcohol (37 grams, 98%) suitable for the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH3:11].CO>CO>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: N
Solvent: CO
Product: N#Cc1cnc(N)nc1Cl
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a stirred solution of 2,4-dichloropyrimidine-5-carbonitrile (500 mg, 2.87 mmol) in MeOH (5 mL) was added 2M NH3/MeOH (5 mL). After stirring for 20 min the resulting precipitate was filtered and washed with MeOH to afford the title compound as a white solid (173 mg, 39%). LCMS (Method C): RT 1.91 min [M+H]+ 155.1. 1H NMR (DMSO-d6, 400 MHz): δ 8.68 (1H, s), 8.23 (2H, br s)
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: O=C(O)c1ccon1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 52 mg, 0.46 mmol, 1.5 equiv), DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) and HATU (175 mg, 0.46 mmol, 1.5 equiv) were added to anhydrous acetonitrile (3 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 8-5 as a white solid. MS m/z (M+H): calculated=422.2188; observed=422.2201. 1H NMR δ (ppm)(CHCl3-d): 8.42 (1H, dd, J=7.77, 1.64 Hz), 7.12 (1H, dd, J=8.03, 1.54 Hz), 7.01 (1H, dd, J=8.02, 4.63 Hz), 6.76 (1H, d, J=1.64 Hz), 6.43 (1H, d, J=13.40 Hz), 4.32 (1H, dd, J=12.00, 8.94 Hz), 4.19 (1H, dd, J=12.14, 2.21 Hz), 4.15-4.08 (1H, m), 4.08 (1H, t, J=8.61 Hz), 4.01-3.85 (1H, m), 3.64 (2H, s), 3.49 (3H, d, J=2.90 Hz), 3.22-3.05 (1H, m), 3.06-2.98 (1H, m), 2.85-2.70 (1H, m), 1.02 (9H, s).
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.C(OC([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24]2[CH:28]=[CH:27][NH:26][C:25]=2C(OCC)=O)[CH2:18][CH2:17]1)=O)(C)(C)C.[Na].Cl>C(Cl)Cl>[NH:16]1[CH2:17][CH2:18][CH:19]([CH2:22][N:23]2[C:24]3[CH:28]=[CH:27][NH:26][C:25]=3[C:4](=[O:5])[NH:6][C:7]2=[S:8])[CH2:20][CH2:21]1
Reactant: CCOC(=O)c1[nH]ccc1NCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)N=C=S
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(CC2CCNCC2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.058 g, 0.44 mmol) was added to a stirred solution of 4-[(2-(ethoxycarbonyl)-1H-pyrrol-3-ylamino)-methyl]piperidine-1-carboxylic acid tert-butyl ester (0.156 g, 0.44 mmol) in CH2Cl2 (2 mL) and the mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue was taken up in ethanol (1 mL) containing sodium (0.015 g, 0.66 mmol). The resulting mixture was heated in a microwave reactor at 120° C. for 10 minutes. 6M HCl (0.5 mL) was added and the reaction mixture was heated again in the microwave at 100° C. for 3 minutes. The pH was adjusted to neutral pH with 2M HCl and the solution was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (0.038 g, 14%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[NH:16][N:15]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:18]=2)=[CH:20][N:21]=1
Reactant: COc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n[nH]2)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C3CCNCC3)n[nH]2)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 4-[5-(6-methoxy-pyridin-3-yl)-1H-[1,2,4]triazol-3-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.23 g, prepared in analogy to intermediate example 44) in THF (15 mL) was treated with 4M HCl in dioxane (1.19 mL) and the reaction stirred at 50° C. for 1 hour. On cooling, the reaction was stirred overnight at rt. The volatiles were removed in vacuo and the residue was dissolved in water, made basic with 2M aqueous NaOH solution and extracted with EtOAc. The aqueous phase was extracted with CH2Cl2/MeOH, the organic phase was washed with brine and concentrated in vacuo to give the crude title compound which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]2[C:16]([OH:18])=[O:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:32]([N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:38](Cl)=[O:39])[CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[CH2:41]([N:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:38]([N:13]1[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:39])[CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCN(CCCCC)C(=O)Cl
Reactant: O=C(O)C1CNCCN1C(=O)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)C(c2ccccc2)c2ccccc2)C(C(=O)O)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 79 mg (0.24 mmole) of (±)-1-(diphenylacetyl)piperazine-2-carboxylic acid (from Example 2, Step A) and 2 ml of THF was treated with 49 mg (0.48 mmole) of triethylamine to give a solution which was cooled to 0° C. With stirring a solution of 61 mg (0.25 mmole) of dipentylcarbamoyl chloride (from Step A) in 0.5 ml of THF was added and the solution was briefly warmed to 50° C. and then stirred at 25° C. for 16 hours. The resulting mixture was filtered and the filtrate was concentrated in vacuo to an oil which was dissolved in 0.5 ml of methanol and was chromatographed over an 85×0.9 cm. LH-20 column with 1.7 ml fractions of methanol. Fractions 21-25 were combined and concentrated in vacuo to 70 mg (57%) of oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:12])=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][CH:7]=[N:6]2.BrBr>C(O)(=O)C>[Br:12][C:4]1[S:3][CH:2]=[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=12
Reactant: O=c1[nH]cnc2c(Br)sc(Br)c12
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cnc2c(Br)scc12

Procedure:
A solution of the product from Example 12 (0.9 g) and bromine (0.3 ml) in glacial acetic acid (100 ml) were heated at 100° C. for 2 hours. On cooling the solvent was removed and the residue was dried. The residue was recrystallised from acetic acid to give the title product, m.p. 226-229° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[C:37](CO)[CH:36]=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(OCC)(=O)C>C(Cl)Cl>[Br:24][CH2:20][C:37]1[CH:36]=[CH:35][N:34]=[C:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Triphenylphosphine (970 mg, 3.7 mmol) and carbon tetrabromide (1.5 g, 4.6 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 690 mg, 3.1 mmol) in methylene chloride (20 mL) under ice-cooling, and the mixture was stirred for 2 hours at room temperature. Ethyl acetate (30 mL) was added to the reaction mixture, the whole was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and brine (20 mL), and then dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate to give 550 mg of the title reference compound as a colorless solid. (Yield 62%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([CH3:16])([NH2:15])[CH3:14])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][C:13]([NH:15][C:26](=[O:28])[CH3:27])([CH3:14])[CH3:16])[C:5]([CH3:17])=[C:4]([CH3:18])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)(C)N)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Cl)c1[N+](=O)[O-]
Reaction time: 2 h
Yield: 83.1 %

Procedure:
A solution of gave N1-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-2-methylpropane-1,2-diamine (3.14 g, 10.9 mmol) in 50 mL of CH2Cl2 was cooled to 0° C. under N2 and treated with triethylamine (2.84 mL, 20.4 mmol) and acetic anhydride (1.01 mL, 10.7 mmol). After stirring for 2 h, the reaction was quenched by the addition of saturated aqueous NaHCO3. CH2Cl2 (100 mL) was added and the organic layer was separated. The organic layer was then washed with cold H2O (2×) and brine. The organic portion was dried with Na2SO4 and concentrated to give N-{2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (2.80 g) as a yellow foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].N1C=CC=CC=1.[C:20]1([C:33](Cl)=[O:34])[C:32]2[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1>ClCCl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:10][C:33]([C:20]2[C:32]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[O:34])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Reactant: Nc1cccc(-c2cnccn2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cnccn2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a suspension of 3-(pyrazin-2-yl)aniline (0.12g) and pyridine (0.17ml) in dichloromethane (3ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.16 g) in dichloromethane (3 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyrazin-2-yl)phenyl)-9H-fluorene-1-carboxamide (0.193 g; 76.0%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@:8]2([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1.C([O-])([O-])=O.[K+].[K+]>C(COC)OC.C(O)(C)(C)C.[Pd]>[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]([C@:8]3([CH3:24])[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[N:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[C:29]([OH:35])=[CH:28][CH:27]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(Br)c2)NC1=NC(=O)OC(C)(C)C
Reactant: OB(O)c1cc(Cl)ccc1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Temperature: 110 °C
Yield: 50 %

Procedure:
A mixture of (S)-tert-butyl 4-(3-bromophenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF2; R1═R6=Me) (0.25 g, 0.6 mmol), 5-chloro-2-hydroxyphenylboronic acid (R21=5-chloro-2-hydroxyphenyl; 0.2 g, 1.2 mmol, 2 eq), Fibrecat (4.26% of Pd, 0.7 g) and 1N aq. K2CO3 (0.5 mL) in dimethoxyethane (DME, 10 mL) or tert-butanol (10 mL) in a 20 mL Smith process vial equipped with stir a bar was sealed and heated in an Emrys optimizer at 110° C. for 15 min. After cooling, the reaction mixture was transferred to a pre-packed Si-Carbonate column and eluted with MeOH/CH2Cl2 (1:1). The eluant was collected and concentrated under reduced pressure to give 0.32 g of the crude product as an oil. The crude product was purified by silica gel chromatography (20-50% EtOAc/hexanes gradient) to yield 0.13 g (0.3 mmol, 48%) of (S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)-phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1═R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1HNMR (CDCl3, 300 MHz): δ 7.48-4.32 (m, 2H), 7.20 (m, 3H), 6.84 (m, 2H), 5.68 (br s, 1H), 3.28 (d, J=15.7 Hz, 1H), 3.21 (s, 3H), 2.96 (d, J=15.3 Hz, 1H), 1.68 (s, 3H), 1.53 (s, 9H). MS (ESI): MH+=443.7, 445.7; M+−56=388.0. HPLC Rt (A)=6.99 min.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH:44][C:45]3[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:55])[F:54])[N:48]=[C:47]([NH:57][C:58]4[CH:66]=[CH:65][C:61]([C:62](O)=[O:63])=[CH:60][CH:59]=4)[N:46]=3)[CH2:43][CH2:42]2)=[CH:37][CH:36]=1.[NH2:67][CH2:68][CH2:69][C@@H:70]([NH:74][C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:71]([OH:73])=[O:72]>CN(C=O)C>[C:78]([O:77][C:75]([NH:74][C@H:70]([CH2:69][CH2:68][NH:67][C:62](=[O:63])[C:61]1[CH:60]=[CH:59][C:58]([NH:57][C:47]2[N:46]=[C:45]([NH:44][C:41]3([C:38]4[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=4)[CH2:43][CH2:42]3)[N:50]=[C:49]([O:51][CH2:52][C:53]([F:56])([F:54])[F:55])[N:48]=2)=[CH:66][CH:65]=1)[C:71]([OH:73])=[O:72])=[O:76])([CH3:81])([CH3:80])[CH3:79]
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCN)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Di-iso-propylethylamine (0.054 g) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.079 g) were added into a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (0.1 g) and (R)-4-amino-2-((tert-butoxycarbonyl)amino)butanoic acid (0.045 g) in DMF (1 mL). The reaction was stirred at room temperature for 16 hours and (R)-2-((tert-butoxycarbonyl)amino)-4-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoic acid was isolated by using preparative HPLC system.
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1cccc(F)c1Br
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C=Cc1ccccc1)Nc1cccc(F)c1Br
Yield: 96 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene. the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(C(=O)CCCCl)cc1C
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCC(=O)c3ccc(C)c(C)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(3,4-dimethylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.2 (M+H)+.