Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:6][CH:5]=1.[N:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.CCN(CC)CC>C1COCC1>[Cl:33][C:31]1[C:30]([Cl:34])=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([C:22]([NH:21][C:12]2[CH:13]=[C:14]([C:17]([F:19])([F:20])[F:18])[CH:15]=[CH:16][C:11]=2[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:41]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:42])=[CH:9][CH:8]=2)=[O:23])[CH:32]=1
Reactant: NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(CNC(=O)N2CCOCC2)cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Into a vial are placed 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride (100 mg, 0.187 mmol), 4-morpholine-carbonylchloride (28 mg, 0.187 mmol), Et3N (0.08 mL, 0.573 mmol), and THF (10 mL). The mixture is heated with efficient stirring at 40° C. for 4 h. The solution is concentrated and purified by preparative thin layer chromatography. The yield is 31 mg of 4,5-dichloro-2-({[2-[(4{[(morpholin-4-ylcarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)benzoic acid, 27%. 1H NMR (400 MHz, DMSO-d6): □ 13.88 (s, 1 H), 10.14 (s, 1 H), 8.09 (s, 2 H), 7.77 (s, 1 H), 7.70 (s, 1 H), 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H) 7.44-7.42 (m, 1 H), 7.26-7.23 (m, 3 H), 7.14-7.09 (m, 3 H), 4.22-4.21 (m, 2 H), 3.56-3.54 (m, 4 H), 3.30-3.28 (m, 4 H). HRMS for C27H23Cl2F3N4O5 m/z 611.1071 M+.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27]>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=3[CH:5]=[N:4][CH:3]=2)=[CH:20][C:19]=1[F:27]
Reactant: CCC(=O)NC1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: CCC(=O)NC1CCCc2c(-c3ccc(Cl)c(F)c3)cncc21
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide (intermediate A-1) was reacted with 4-chloro-3-fluorophenylboronic acid to give the title compound as light brown foam in 83% yield. MS: 333.4 (M+H+, 1Cl).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([OH:18])=O)[CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([N:22]([CH:19]2[CH2:21][CH2:20]2)[C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:11]2)=[O:18])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reactant: C1CCC(NC2CC2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C1CCCN(S(=O)(=O)c2ccccc2)C1)N(C1CCCCC1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(phenylsulfonyl)piperidine-3-carboxylic acid (20 mg), N-cyclopropylcyclohexanamine (10 mg) and benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (36 mg) in DMF (200 μL) was added N,N-diisopropylethylamine (26 μL). The resulting solution was stirred at r.t. for 2 hours and directly purified with prep HPLC. LCMS m/z 391.1 (M+H)+; 803.2 (2M+Na)+.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[NH:8][C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[N:8]([CH3:27])[C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCC(CC)n1c(=O)[nH]c2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)n1c(=O)n(C)c2c(Oc3c(C)cc(C)cc3C)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.9 %

Procedure:
A solution of 1-(1-ethylpropyl)-6-methyl-4-(2,4,6-trimethylphenoxy)-1,3-dihydro-imidazo[4,5-c]pyridin-2-one (100 mg, 0.28 mmol) in 5 ml of dry THF was treated with lithium bis(trimethylsilyl)amide (0.31 ml, 1 M in THF, 0.31 mmol) at −78° C. After 20 min, the mixture was quenched with 1 ml of methyl iodide and stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give 110 mg of an off-white solid which was recrystallized from isopropyl ether to give white crystals. Mp 152–154° C.; 1H NMR (CDCl3) δ 6.91 (s, 2H), 6.57 (s, 1H), 4.18 (m, 1H), 3.73 (s, 3H), 2.32 (s, 3H), 2.27 (s, 3H), 2.12 (s, 6H), 1.9–2.1 (m, 2H), 1.7–1.9 (m, 2H), 0.88 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)nc2)C1
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ccc(Cl)cn3)nc2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
tert-Butyl (RS)-2-(6-aminopyridin-3-yl)morpholine-4-carboxylate (55 mg), 2,5-dichloropyridine (29 mg, CAS 16110-09-1) and cesium carbonate (96 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (6.84 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.11 mg) were then added. The reaction mixture was then capped and stirred at 100° C. overnight. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl 2-(6-(5-chloropyridin-2-ylamino)pyridin-3-yl)morpholine-4-carboxylate (22 mg, 29%) as a yellow solid. MS (ISP): 393.2 ([{37Cl}M+H]+), 391.2 ([{35Cl}M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:14]1([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=3[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CC1=Cc2cc(Br)ccc2OC1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Product: O=CC1=Cc2cc(-c3ccccc3)ccc2OC1

Procedure:
The starting material is prepared as follows: 6-Bromo-2H-1-benzopyran-3-carboxaldehyde (5.00 g, 20.9 mmol), phenylboronic acid (2.81 g, 23.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (725 mg, 0.63 mmol) are dissolved in 50 ml of toluene and treated with 25 ml of aqueous 2M sodium carbonate under nitrogen. The mixture is heated at reflux for 6 hours. The reaction mixture is cooled and extracted with ether (3×). The combined ethereal extracts are dried (MgSO4) and evaporated. Flash chromatography (silica gel, 5% ethyl acetate/hexane), yields 6-phenyl-2H-1-benzopyran-3-carboxaldehyde, m.p. 108°-110° C., which is converted to the final product as described above.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].O>CO>[NH2:18][C:6]1[CH:5]=[C:4]([S:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[NH:10][C:11]([NH:13][C:14]([O:16][CH3:17])=[O:15])=[S:12]
Reactant: CCSc1ccc(NC(=S)NC(=O)OC)c([N+](=O)[O-])c1
Solvent: O
Solvent: CO
Product: CCSc1ccc(NC(=S)NC(=O)OC)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
A mixture of 4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene (14.0 g), ferrous chloride tetrahydrate (3.04 g), methanol (235 ml) and water (50 ml) was heated to reflux and treated with reduced iron powder (15.5 g) portionwise during 5 minutes. The mixture was heated at reflux with stirring for one hour. Methanol (250 ml) was added and the mixture was again heated to reflux. The hot mixture was filtered and the filtrate was allowed to cool to room temperature. The solid which crystallised on cooling was filtered off to give 2-amino-4-ethylthio-1-(3-methoxycarbonyl-2-thioureido)benzene (7.5 g), m.p. 168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:33]([F:40])[C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH:33]([F:40])[C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36])[CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reactant: O=C(O)C(F)(F)C(F)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(F)C(F)(F)C(=O)O)c3)no2)cc1Cl
Temperature: 140 °C
Reaction time: 10 h
Yield: 4.4 %

Procedure:
D5 (200 mg), Cs2CO3 (552 mg) and DMF (2.8 ml) were stirred at RT and treated with 3-bromo-2,2,3-trifluoropropanoic acid (175 mg). This mixture was heated at 140° C. for 1 hour in a microwave reactor. 2 further equivalents of Cs2CO3 (368 mg) were added and heating continued at 140° C. for 10 hours. The reaction mixture was then evaporated, treated with H2O, shaken and filtered to give a brown solid residue. This was purified by MDAP to give the title compound (12 mg) as a white solid. δH (methanol-d4, 400 MHz): 1.42 (6H, d), 4.83 (1H, septet), 6.87 (1H, d), 7.29 (1H, d), 7.45 (1H, d), 7.54 (1H, d), 7.61 (1H, d), 7.80 (1H, d), 8.06 (1H, d), 8.11 (1H, d), 8.19-8.22 (1H, m), 8.44 (1H, s).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[N:11]=[N:10][C:9]([CH3:12])=[C:8]2[N:13]=[CH:14][NH:15][C:7]=12.S(=O)(=O)(O)[OH:17]>O.C(O)(=O)C>[CH3:12][C:9]1[C:8]2[N:13]=[CH:14][NH:15][C:7]=2[C:6](=[O:17])[NH:11][N:10]=1
Reactant: Cc1nnc(N)c2[nH]cnc12
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)c2[nH]cnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 4.00 g sodium nitrite in 15 ml of water is added dropwise at 50° C. to 2.20 g of 4-amino-7-methyl-3H-imidazo[4,5-d]pyridazine in a mixture of 30 ml acetic acid, 5 ml of water and 0.5 ml concentrated sulphuric acid. The reaction mixture is stirred for a further two hours at 50° C. and then heated to 90° C. for one hour. After cooling to ambient temperature the reaction mixture is diluted with 30 ml of water. The precipitate formed is suction filtered, washed with water, ethanol and diethyl ether and dried.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.C(OC([NH:37][C:38]1[CH:39]=[C:40]([CH3:59])[C:41]([N:44](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:42][CH:43]=1)=O)(C)(C)C>>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:44][C:41]3[C:40]([CH3:59])=[CH:39][C:38]([NH2:37])=[CH:43][N:42]=3)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Product: Cc1cc(N)cnc1NCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 of Example 11 from 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and di-tert-butyl {5-[(tert-butoxycarbonyl)amino]-3-methylpyridin-2-yl}imidodicarbonate from Step 2 of this example.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[C:32](Cl)(=[O:41])[C:33]1[C:34]([O:39][CH3:40])=[CH:35][CH:36]=[CH:37][CH:38]=1.O>O1CCCC1.[H-].[Na+]>[CH3:40][O:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]([N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)=[O:41]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)N(Cc2ccccn2)C(=O)c2ccccc2OC)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a solution of 1 g of product from Example 4 in 15 ml of dry tetrahydrofuran is added in one portion 0.0622 g of sodium hydride. The mixture is heated at reflux temperature for 2 hours, cooled to room temperature and 0.442 g o-anisoyl chloride is added. The reaction is then heated at reflux for 1.5 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 35% ethyl acetate/hexane) to give 1.27 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([OH:32])(=O)=[O:30])[CH:8]=2)[N:3]=1.S(Cl)([Cl:35])=O>CN(C=O)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([Cl:35])(=[O:32])=[O:30])[CH:8]=2)[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)O)ccc2n1
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(=O)(=O)Cl)ccc2n1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
40 ml of thionyl chloride together with one drop of DMF are added to a solution of 5 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonic acid. The mixture is stirred at 22° C. for 16 h, evaporated in vacuo, taken up in 500 ml of DCM and extracted twice with 300 ml of water each time. The organic phase is dried over magnesium sulfate, filtered off and evaporated to dryness in vacuo. The residue is employed in the following steps without further purification. Yield: 6.9 g (98%) of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzenesulfonyl chloride;
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[C:15]([Br:17])[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2sccc2C(C)C1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2sc(Br)cc2C(C)C1
Reaction time: 0.25 h

Procedure:
The product of step d) (80 mg, 0.35 mmol) was dissolved in 2 mL of 1:1 CHCl3 /HOAc. N-Bromo-succinimide (62 mg, 0.35 mmol) was added and the reaction was stirred for 15 minutes. Concentration and purification by silica gel chromatography gave the subtitle compound as a yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:11]([OH:22])[CH2:12][NH:13][CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:40]1[C:44]2[CH:45]=[CH:46][C:47]([S:49](Cl)(=[O:51])=[O:50])=[CH:48][C:43]=2[O:42][CH2:41]1>C(Cl)Cl>[O:1]1[CH2:6][CH:5]([O:7][C:8](=[O:30])[NH:9][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:11]([OH:22])[CH2:12][N:13]([S:49]([C:47]2[CH:46]=[CH:45][C:44]3[O:40][CH2:41][O:42][C:43]=3[CH:48]=2)(=[O:50])=[O:51])[CH2:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][C:18]#[N:19])[CH2:4][O:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCO2
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC1COCOC1)S(=O)(=O)c1ccc2c(c1)OCO2
Yield: 73.4 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethyl-butylamino)-2-hydroxy-propyl]-carbamic acid[1,3]dioxan-5-yl ester (0.059 g, 0.14 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (0.075 ml, 0.42 mmol) and Benzo[1,3]dioxole-5-sulfonyl chloride (0.037 g, 0.17 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (1% to 3% MeOH in CH2Cl2) gave 0.062 g of a white solid. MS(ES): 604 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:6][CH:5]=1)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH:11]2[C:14]([F:27])([F:26])[C:15]([N:17]([F:25])[CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)C(C(F)(F)C(=O)N(F)Cc1ccccc1)CCC2
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(7-nitro-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifluoroacetamide (2.55 g, 6.75 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(7-amino-(1,2,3,4-tetrahydronaphthyl))-N-(phenylmethyl)trifluoroacetamide which was homogeneous by TLC and used immediately in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39][CH:40]([C:44](O)=[O:45])[C:41](O)=[O:42])([CH3:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:10][C:41](=[O:42])[C:40]([S:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH:30]([CH3:31])[CH3:32])=[C:44]([OH:45])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2cccc(Cl)c2)oc1=O
Yield: 70 %

Procedure:
The title compound was prepared by Method A using 3'-chloroacetophenone (3 g, 19.41 mmol), trimethylsilyl triflate (4.31 g, 19.41 mmol), triethylamine (3.92 g, 38.82 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio]-propanedioic acid (3.0 g, 9.71 mmol). Isolated yield: 70% m.p. 177-178° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 6H), 3.42 (m, 1H), 6.92 (d, 1H), 6.94 (s, 1H), 7.06 (t, 1H), 7.13 (t, 1H), 7.28 (d, 1H), 7.58 (t, 1H), 7.63 (t, 1H), 7.83 (d, 1H), 7.89 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>O>[CH:25]1[CH:24]=[C:21]2[C:22]([N:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=1)=[O:23]
Reactant: NCCC(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 63.5 %

Procedure:
To a stirred mixture of β-alanine (4.45 g, 50.0 mmol) and sodium carbonate (5.35 g, 50.5 mmol) in 100 mL of water is added N-carbethoxyphthalimide (10.95 g, 50.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. After 15 minutes, the resulting slurry is filtered and the solid washed with water. The solid is dried in vacuo (60° C., <1 mm) to afford 6.96 g (64%) of N-phthaloyl-β-alanine, which can be alternatively named as 3-phthalimido-3-phenylpropionic acid, as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([O-:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Na+].[F:19][C:20]([F:41])([F:40])[C:21]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)([OH:26])[C:22]([F:25])([F:24])[F:23].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:37]3[CH2:38][CH2:39][N:34]([CH2:33][C:30]4[CH:31]=[CH:32][C:27]([C:21]([OH:26])([C:22]([F:23])([F:24])[F:25])[C:20]([F:41])([F:19])[F:40])=[CH:28][CH:29]=4)[CH2:35][CH2:36]3)=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cc1ccc(C(=O)[O-])cc1)NCC1CC1
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1)NCC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 1.9 %

Procedure:
Sodium 4-(2-(cyclopropylmethylamino)-2-oxoethyl)benzoate (5.26 mmol, 1.342 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (5.26 mmol, 1.800 g), and triethylamine (18.40 mmol, 2.56 mL, 1.862 g) were combined in dichloromethane (25 mL) and the reaction mixture stirred at room temperature for 15 minutes. 1-Propanephosphonic acid cyclic anhydride (7.89 mmol, 4.69 ml, 5.02 g; 50% solution in ethyl acetate) was added dropwise and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer was separated and concentrated under vacuum to obtain crude product. The crude product was purified by SCX column chromatography, silica column chromatography (eluting with 90:10:1 dichloromethane/methanol/ammonia) and acidic preparative HPLC to afford the title compound (55.3 mg). MS (ESI) m/z 558.2 [M+H]+