Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH2:63])[CH2:56][C:57]3[CH:62]=[CH:61][N:60]=[CH:59][CH:58]=3)=[N:54][C:50]=2[CH:49]=1>CN(C)C=O>[Cl:47][C:48]1[CH:65]=[CH:64][C:51]2[NH:52][C:53]([C@@H:55]([NH:63][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:56][C:57]3[CH:58]=[CH:59][N:60]=[CH:61][CH:62]=3)=[N:54][C:50]=2[CH:49]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](Cc1ccncc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](Cc2ccncc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 0.150 g (0.579 mmol) of 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, 0.186 g (0.579 mmol) of TBTU, and 0.20 mL (1.78 mmol) of N-methylmorpholine in 2 mL of N,N-dimethylformamide is stirred for 10 minutes at ambient temperature and then combined with a solution of 0.158 g (0.579 mmol) of (S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-pyridin-4-ylethylamine. The reaction mixture is stirred for one day at ambient temperature, then poured onto ice water and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate and concentrated. The residue is chromatographed on silica gel, eluting with dichloromethane/methanol (95:10). Yield: 61.5 mg (22% of theory); Rf value: 0.44 (silica gel; dichloromethane/methanol=9:1); C27H26ClN5O2 (487.99); mass spectrum: (M−H)−=486/488 (chlorine isotope).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[N:22][C:9]=3[N:10]=[C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>CO.[Pd]>[N:1]1([C:7]2[C:8]3[CH:25]=[C:24]([NH2:26])[CH:23]=[N:22][C:9]=3[N:10]=[C:11]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2nc(OCCN3CCOCC3)nc(N3CCOCC3)c2c1
Reaction time: 5 h
Yield: 46.9 %

Procedure:
4-Morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-nitro-pyrido[2,3-d]pyrimidine (3.35 g) was dissolved in methanol (100 mL), and to the solution was added 5% palladium on carbon (100 mg). The suspension was placed under an atmosphere of hydrogen, and stirred for five hours. The solution was filtered and evaporated, and then purified by column chromatography to give 4-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-6-amino-pyrido[2,3-d]pyrimidine (1.45 g) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@@H:11]([O:19][CH:20]([CH3:22])[CH3:21])[C@@H:10]1[OH:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([O:19][CH:20]([CH3:21])[CH3:22])[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)O[C@@H]1c2ccccc2C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)OC1C(=O)C(NC(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Yield: 76.5 %

Procedure:
Under argon to a solution of (±)-(1R,2R,3R)-3-tert-butoxycarbonylamino -1,2,3,4-tetrahydro-1-isopropyloxy-2-naphthalenol (50 mg) in anhydrous methylene chloride (4 ml) was added Dess-Martin periodinane (100 mg). Agitation was maintained at room temperature for 2 hours. The reaction mixture was filtered on a silica gel column (10 g, elution ethyl acetate:cyclohexane, 1:9) to afford the title compound as an oil (38 mg).
Reaction SMILES: Br[CH2:2][CH:3]([N:10]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=2[N:12]=[C:11]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH:28][C:29]1[CH:34]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:32]=[CH:31][N:30]=1.CCCCCCC>C(OCC)(=O)C>[CH3:38][O:37][C:35](=[O:36])[C:33]1[CH:32]=[CH:31][N:30]=[C:29]([O:28][CH2:2][CH:3]([N:10]2[C:14]3[CH:15]=[C:16]([F:20])[C:17]([F:19])=[CH:18][C:13]=3[N:12]=[C:11]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:34]=1
Reactant: COC(=O)c1ccnc(O)c1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CBr)C3CCCCC3)c2cc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 35 from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Ex. 34, int.) and methyl 2-hydroxypyridine-4-carboxylate after a reaction time of 4 days at room temperature and using a gradient of n-heptane:ethyl acetate of 100:0 to 70:30. Light yellow solid (19%). MS: (Turbo Spray): m/z=526.2 [M+H].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([O:12]CC)=[O:11])=[CH:5][N:4]=1.[OH-].[Na+].Cl>O>[F:16][C:2]([F:1])([F:15])[C:3]1[N:8]=[C:7]([OH:9])[C:6]([C:10]([OH:12])=[O:11])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(C(F)(F)F)nc1O
Yield: 52 %

Procedure:
A solution of ethyl 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylate (5.00 g, 19.4 mmol) and NaOH (0.93 g, 23.3 mmol) in H2O (20 mL) was stirred at 60° C. for 15 h. The reaction was acidified (concentrated HCl) and concentrated until a solid began to form. The solid was filtered and dried to give 2-trifluoromethyl-4-hydroxypyrimidine-5-carboxylic acid (2.1 g, 53% yield); 1H NMR (DMSO-d6) δ 8.83 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)[C:18](Cl)=[O:19]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([CH:18]=[O:19])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=Cc1cc2ccc(-c3ccc(F)cc3)cc2[nH]1

Procedure:
The desired compound was prepared by Vilsmeier formylation of 6-(4-fluorophenyl)indole using DMF and oxalyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][O:25][CH:26]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-furansulfonyl chloride (43 mg, 0.256 mmol), the title compound was obtained as a white solid (71 mg, 61% yield). MS (ESI): 474.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][NH2:12])=[N:9][CH:10]=1)(=[O:4])=[O:3].C(O)(C)C.[F:17][CH:18]([F:30])[C:19](=O)[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O.S(=O)(=O)(O)O>O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][C:19]([CH:18]([F:17])[F:30])=[N:12]2)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)F)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccccc2)nc1
Reaction time: 0.25 h

Procedure:
To 120 g of 5-(methylsulfonyl)-2-hydrazinyl-pyridine [CP-675,775] (0.641 moles) was charged isopropanol (900 mL) followed by 4,4-difluoro-1-phenyl-1,3-butanedione (122 g, 0.615 moles, 0.96 eq.) as a melt, followed by 900 mL of isopropanol. The slurry was stirred for 15 minutes, then 36 mL of concentrated sulfuric acid was added (slight exotherm) (15 volumes of isopropanol total). The reaction was stirred for 6 hours at 20-30° C., 2.4 L (20 volumes) of water was added (slight exotherm, reaction temperature kept below 45° C.) and the reaction was granulated for 2 days. The product was filtered and was rinsed with water. The product contained less than 0.5% of compound 6 (retention time 5.1 minutes). Analytical data: HPLC retention time (title compound) 8.4 minutes; MS: 349.36 (calc), M+1=350.1; 1H NMR in CDCl3: 8.75 doublet, (1H), 8.26 Quartet (1H), 7.38 multiplet (3H), 7.36 doublet (2H), 6.70 multiplet (2H), 3.08, Singlet, (3H); 13C NMR in CDCl3: 15.3, 149.3, 147.9, 146.6, 138.1, 130.27, 133.5, 130.0, 129.1, 128.7, 117.9, 113.4, 111.1, 108.1, 107.7, 45.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:5]1[CH:6]=[C:2]([C:19]2[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=2)[C:13]#[N:14])[CH:3]=[N:4]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Brc1cnn(-c2ccccn2)c1
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: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2cnn(-c3ccccn3)c2)c1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(4bromo-1H-pyrazol-1-yl)pyridine (0.446 g, 2.0 mmol), 3-cyanophenylboronic acid (0.302 g, 2.0 mmol), potassium carbonate (0.552 g, 4.0 mmol) in a mixture of ethylene glycol dimethyl ether (20 mL) and water (4 mL) was degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added and degassing continued a further 15 min. The resulting solution was stirred at 70° C. for 14 h, whereupon H2O (30 mL) was added, then extracted with EtOAc (3×30 mL) and the combined extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from EtOAc/Hexane give 3-(1-pyridin-2-yl-1H-pyrazol-4-yl)benzonitrile as a white solid. MP=160-161° C. 1H NMR (CD3Cl, 300 MHz) δ 8.88 (s, 1H), 8.45 (d, 1H), 8.03 (s, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.86 (s, 1H), 7.81 (d, 1H), 7.57˜7.48 (m, 2H), 7.25 (dd, 1H). MS (ESI) 247.1 (M++H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][C:31]1[S:35][C:34]([C:36]([OH:38])=O)=[CH:33][CH:32]=1>>[CH3:30][C:31]1[S:35][C:34]([C:36]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:38])=[CH:33][CH:32]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: Cc1ccc(C(=O)O)s1
Agent: Cl
Product: Cc1ccc(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)s1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 5-methyl-2-thiophenecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(5-methyl-2-thiophenecarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 488 (M-H)-.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]([OH:21])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC1C(O)=C(F)C(F)=C(F)C=1F.[CH3:34][N:35]1CCOCC1.CN.C(O)C>C(Cl)Cl>[CH3:34][NH:35][C:19](=[O:21])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CN
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of N-Boc-4-cyanophenylalanine (1.92 g, 6.6 mmol) and pentafluorophenol (2.43 g, 13.2 mmol) in CH2Cl2 (30 ml) at 0° C. was treated with 4-methylmorpholine (0.74 g, 7.3 mmol). After stirring the reaction mixture for 3 hours, 8M methylamine in ethanol (15 ml, 19.8 mmol) was added and the reaction mixture left to stir at room temperature for 16 hours. The solvent was removed under pressure, the residue dissolved in CH2Cl2 (50 ml) and washed with saturated sodium bicarbonate (2×50 ml), 1M citric acid (2×50 ml) and brine (50 ml). The CH2Cl2 layer was dried over MgSO4 and the solvent removed under pressure to yield the title compound as a white solid (1.84 g, 92%).
Reaction SMILES: [C:1](O)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][C:25]([CH3:38])([CH2:36][CH3:37])[C:26](=[O:35])[C:27]([CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][NH:30]1)=[O:28]>>[C:1]([N:30]1[CH:29]([C:27](=[O:28])[C:26](=[O:35])[C:25]([CH3:38])([CH3:24])[CH2:36][CH3:37])[CH2:34][CH2:33][CH2:32][NH:31]1)(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6]
Reactant: C#CCCCC(=O)O
Reactant: CCC(C)(C)C(=O)C(=O)C1CCCNN1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: C#CCCCC(=O)N1NCCCC1C(=O)C(=O)C(C)(C)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.8 %

Procedure:
To a solution of 5-hexynoic acid (0.467 g, 4 mmol) in 10 ml CH2Cl2was added triethylamine (0.56 ml, 4 mmol), followed by isobutyl chloroformate (0.53 ml, 4 mmol) at 0° C. After stirring for 5 minutes, a solution of 3,3-dimethyl-1-perhydropyridazinyl pentane-1,2-dione (0.424 g, 2 mmol) in 1 ml CH2Cl2was added. The reaction was gradually warmed up to room temperature. The crude material was subject to silica gel purification to yield final product as clear oil (0.385 g, 63%). 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, 3H, J=7.0); 1.26 (s, 6H); 1.76(m, 8H); 2.28 (m, 2H); 2.50 (m, 2H); 2.88 (m, 2H); 3.60 (m, 1H); 4.50 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[C:12]1([S:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>C(Cl)(Cl)Cl>[CH3:19][S:18][C:12]1[CH:17]=[CH:16][C:15]([C:7](=[O:8])[CH:6]([CH3:5])[CH2:10][CH3:11])=[CH:14][CH:13]=1
Reactant: CSc1ccccc1
Reactant: CCC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC(C)C(=O)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of AlCl3 (35.4 g) in CHCl3 (500 mL) at −10° C. was added dropwise 2-methylbutyryl chloride (3.13 g) followed by thioanisole (31.2 mL). The mixture was then stirred at r.t. for 20 min. and was then cooled back to 0° C. Water (200 mL) was then added over 30 min. The CHCl3 layer was separated and dried over MgSO4. After filtration and removal of the solvent, the residue was dried under vacuum at 80° C. for 2 h to give 35 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)C>CN(C=O)C>[C:14]([Si:11]([CH3:13])([CH3:12])[O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Yield: 100 %

Procedure:
A solution of 5-hydroxy-indole (5 g, 38 mmol), tert-butyldimethylsilyl chloride (6.13 g, 39.4 mmol) and imidazole (5.37 g, 68.1 mmol) in DMF (50 ml) was stirred for 20 h at RT. Diethyl ether was added and the mixture was washed wih 1N HCl and water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 9.4 g (38 mmol, quant.) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C:13]2[C:22]([NH:23][C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[CH:25]=3)=[N:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:34]=[N+:35]=[N-:36].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[CH3:31][O:30][C:28]1[CH:29]=[C:24]([NH:23][C:22]2[C:13]([NH:12][S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]4[N:34]=[N:35][NH:36][N:2]=4)[CH:4]=3)(=[O:10])=[O:11])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:25]=[C:26]([O:32][CH3:33])[CH:27]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(C#N)c2)cc(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(-c3nn[nH]n3)c2)cc(OC)c1
Temperature: 25 °C
Yield: 24.8 %

Procedure:
To a stirred solution of 3-cyano-N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)benzenesulfonamide (0.20 g, 0.44 mmol) in dimethylformamide (1.2 mL) at 50° C. were added sodium azide (0.11 g, 1.76 mmol) and ammonium chloride (94 mg, 1.76 mmol). The crude mixture was heated at 100° C. overnight. The reaction was cooled to room temperature treated with ice water (20 mL) followed by concentrated hydrochloric acid (10 mL). The solid obtained was filtered under reduced pressure and washed with hexane (20 mL), diethyl ether (20 mL), and ethyl acetate (5 mL) to afford N-(3-{[3,5-bis(methyloxy)phenyl]amino}quinoxalin-2-yl)-3-(2H-tetrazol-5-yl)benzenesulfonamide (55 mg, 25%) as light yellow solid. MS (EI) for C23H20N8O4S: 505.0 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23]=3Br)[C:18]2=[O:31])=[CH:12][CH:11]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1(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)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:18]2=[O:31])=[CH:12][CH:11]=1
Reactant: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(c(-c3ccccc3)c1OC)CN(Cc1ccc(C(=O)Nc3ccccc3N)cc1)C2=O
Yield: 92.9 %

Procedure:
N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzamide (60 mg, 0.12 mmol) in Example 1, phenyl boronic acid (22 mg, 0.18 mmol, 1.5 equiv.), tetrakis(triphenyl-phosphino)palladium (8.4 mg, 0.0073 mmol, 6 mol %) and sodium carbonate (38 mg, 0.36 mmol, 3 equiv.) were dissolved in a mixture of dioxane and the distilled water (mixture ratio=4:1 (v/v), 5.0 mL) and the resulting solution was reacted at 150° C. under microwave for 15 mins. The resulting material thus obtained was diluted with ethyl acetate (EtOAc), dried over anhydrous MgSO4, and filtered with Celite. The filtrates were distilled under a reduced pressure to remove the solvent and the resulting residue was subjected to a silica gel column chromatography (EtOAc) to obtain the title compound (55 mg, 92%).
Reaction SMILES: C[Mg+].[Br-].[C:4]1(C)C=CC=CC=1.C1COCC1.[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([CH:27]=[CH:28][C:29]3[CH:30]=[C:31]([C@H:35]([OH:48])[CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][CH:45]=[CH:44][C:39]=4[C:40]([O:42]C)=O)[CH:32]=[CH:33][CH:34]=3)=[N:24]2)=[CH:19][CH:18]=1.CO>C1COCC1.O>[C:40]([C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][C:38]=1[CH2:37][CH2:36][C@H:35]([C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH:28]=[CH:27][C:23]2[CH:22]=[CH:21][C:20]3[C:25](=[CH:26][C:17]([Cl:16])=[CH:18][CH:19]=3)[N:24]=2)[CH:30]=1)[OH:48])(=[O:42])[CH3:4]
Reactant: COC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Reactant: Cc1ccccc1
Agent: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccccc1CC[C@@H](O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
At 0° C., a 1.5M MeMgBr solution in toluene:THF 1:1 (130 mL, 195 mmol) was added dropwise to a solution of the hydroxyester of Step 3 (11.04 g, 24.1 mmol) (dried in EtOAc and stripped with toluene to remove the H2O) and MeOH (2.0 mL, 49.4 mmol) in 240 mL of anhydrous THF. The reaction mixture was stirred at r.t. for 2.5 h and was then poured into ice cold 25% NH4OAc. The product was extracted into EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with EtOAc:toluene 10:90 and 15:85. [α]D : +23.8° (c=1.04, CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:8]1([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][S:10][CH2:11][C@H:12]1[C:13]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CSCC1C(=O)O
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.10 g of N-(t-butoxy-carbonyl)-1,3-thiazolidine-4-carboxylic acid, 45 μl of tert-butylamine, 66 mg of HOBt and 98 mg of EDC hydrochloride were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 34 (Process 3) to give 90 mg of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:13]([C:14]([C:23]([C:25]3[CH:26]=[CH:27][C:28]4[N:33]=C(C5C=CC=CC=5)[O:31][C:30](=[O:40])[C:29]=4[CH:41]=3)=[O:24])=[C:15]([CH3:22])[C:16]=2[O:20][CH3:21])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.CN1CCCC1=O>[NH2:33][C:28]1[CH:27]=[CH:26][C:25]([C:23]([C:14]2[N:13]3[C:17]([CH:18]=[CH:19][C:11]([O:10][CH2:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:12]3)=[C:16]([O:20][CH3:21])[C:15]=2[CH3:22])=[O:24])=[CH:41][C:29]=1[C:30]([OH:40])=[O:31]
Reactant: COc1c(C)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2cc(OCc3ccccc3)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1c(C)c(C(=O)c2ccc(N)c(C(=O)O)c2)n2cc(OCc3ccccc3)ccc12
Yield: 69 %

Procedure:
A solution of 2.17 g (38.7 mmol) of potassium hydroxide in 6 ml of water is added to the suspension of 2.0 g (3.87 mmol) of 6-{[6-(benzyloxy)-1-methoxy-2-methylindolizin-3-yl]carbonyl}-2-phenyl-4H-3,1-benzoxazin-4-one in 15 ml of N-methyl-2-pyrrolidone at ambient temperature. The mixture is brought to reflux for 4 hours. After cooling, the reaction medium is poured into an aqueous solution of hydrochloric acid (0.1 M). The precipitate formed is filtered and washed thoroughly with water and then with diisopropyl ether. 1.15 g (70%) of a yellow powder are obtained after drying under vacuum at 50° C.