Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[B:38]1(B2OC(C)(C)C(C)(C)O2)[O:42]C(C)(C)C(C)(C)[O:39]1.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([B:38]([OH:42])[OH:39])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: O=c1c2cc(B(O)O)ccc2ccc2ncc(Cl)cc12
Temperature: 95 °C
Reaction time: 6 h

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.00 g, 3.12 mmol), Pd2(dba)3 (0.146 g, 0.16 mmol), tricyclohexylphosphine (0.104 g, 0.37 mmol), bis(pinacolato)diboron (0.87 g, 3.43 mmol) and potassium acetate (0.61 g, 6.23 mmol) were mixed in a dry flask through which argon was purged. The flask was charged with 40 mL of dry dioxane and argon was bubbled through the solution for 15 minutes. The reaction was heated to 95° C. and stirred under argon. After 6 h, the reaction mixture was poured into 500 mL of ethyl acetate and 100 mL of saturated aqueous ammonium chloride. The organic layer was separated, dried with magnesium sulfate, filtered, and concentrated to afford the title compound. LRMS (APCI) calculated for C14H10BClNO3 [M+H]+, 286.0; found 286.1.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:24]1[N:25]=[C:26]([NH2:42])[C:27]2[N:28]=[CH:29][N:30]([C:40]=2[N:41]=1)[C@@H:31]1[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]1[OH:33]>>[CH3:22][O:21][C:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][C:10]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[C:3][C:24]3[N:25]=[C:26]([NH2:42])[C:27]4[N:28]=[CH:29][N:30]([C:40]=4[N:41]=3)[C@@H:31]3[O:39][C@H:36]([CH2:37][OH:38])[C@@H:34]([OH:35])[C@H:32]3[OH:33])[CH2:5][CH2:6]2)=[O:11])=[CH:18][CH:17]=1)=[O:20]
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C(=O)OC)cc2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: COC(=O)c1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1

Procedure:
Batch: AB-9-151. 4-(methoxycarbonyl)phenyl 4-(prop-2-ynyl)piperidine-1-carboxylate, batch JR28-85 (0.670 g, 2.223 mmol) was added to a solution of 2-iodoadenosine (0.675 g, 1.717 mmol) according to general procedure 2. Yield: 0.648 g, 67%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 8.04-7.20 (2×m, 4H), 5.94 (d, 1H), 4.69 (m, 2H), 4.32-3.71 (4×m, 8H), 3.91-2.71 (2×d, 2H), 3.16-2.90 (2×bt, 4H), 2.48 (d, 5H), 1.98-1.45 (2×m, 5H). m/z MH+=567.14. HPLC rt=7.9 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:12])[C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:13][NH:14][CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:12])[C:9]([N:14]([CH3:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)c1cccc(Br)c1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)C(=O)C(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A mixture of (3-bromo-phenyl)-fluoro-acetic acid (436 mg, 1.9 mmol), dimethyl amine (1.9 ml, 3.7 mmol-2M solution in THF), HATU (1.1 g, 2.8 mmol), DIEA (0.7 ml, 3.7 mmol) in DMF were stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with 1N HCl, saturated Na2HCO3, brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-(3-bromo-phenyl)-2-fluoro-N,N-dimethyl-acetamide (212 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.86 (d, 6H), 6.40-6.44 (d, 1H), 7.41 (m, 1H), 7.45 (d, 1H), 7.642 (m, 2H). MS: m/z 261.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:8]=[N:9][C:10]([NH2:13])=[CH:11][CH:12]=1)([CH3:6])[CH3:5].Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:7]1[CH:8]=[N:9][C:10]([NH:13][C:16]2[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)c1ccc(N)nc1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)C(C)(C)c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Yield: 61.5 %

Procedure:
2-(6-Amino-pyridin-3-yl)-2-methyl-propionic acid methyl ester (1.5 g, 7.7 mmol), 3,5- dibromo-1-methyl-1H-pyridin-2-one (2.05 g, 7.7 mmol), cesium carbonate (7.53 g, 23.1 mmol), bis(dibenzylideneacetone)palladium (353 mg, 0.385 mmol), and Xantphos (446 mg, 0.77 mmol) were added to a round bottom flask and the flask was purged with nitrogen. Degassed dioxane (50 ml) was added through a syringe. The reaction mixture was heated at 100 degrees centigrade overnight. The reaction mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography using a gradient of 0% to 50% ethyl acetate in hexanes to give 1.8 g (62%) of 2-[6-(5-bromo-1-methyl-2-oxo-1,2-dihydro-pyridin-3-ylamino)-pyridin-3-yl]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:36])=[C:20]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:29])([F:28])[F:27])[CH3:25]>O.O1CCOCC1>[Cl:36][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:34]([Cl:35])[CH:33]=[CH:32][C:20]=1[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:27])([F:28])[F:29])[CH3:25]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: CC(C)(C(=O)NCc1ccc(Cl)c(N)c1Cl)C(F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl)C(F)(F)F

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (3.12 g, 13 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-trifluoromethyl-propionamide (3.90 g, 11.8 mmol) and dioxane (135 mL) and stirred at reflux overnight. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH3:39])=[N:36]2)=[CH:31][CH:30]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([CH3:39])=[N:36]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Yield: 81.4 %

Procedure:
Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)quinazoline (156 mg, 0.38 mmol), (prepared as described for the starting material in Example 12), was reacted with 7-hydroxy-2-methylquinoline (66 mg, 0.4 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-(2-methylsulphonylethyl)piperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (166 mg, 82%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12]([C:19]([OH:21])=O)=[CH:13][CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:19]([C:12]1[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])=[C:16]([O:17][CH3:18])[CH:15]=[CH:14][CH:13]=1)=[O:21])[CH3:27]
Reactant: CCNCC
Reactant: COc1cccc(C(=O)O)c1-c1ccccc1OC(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cccc(OC)c1-c1ccccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111.3 %

Procedure:
Prepare a stirred solution of 2'-isopropoxy-6-methoxy-biphenyl-2-carboxylic acid (1.432 g, 0.0050 mole) in methylene chloride (50 mL) at -50° C. and under argon. Warm to ambient temperature then add thionyl chloride (0.8415 g, 0.516 mL). Continue stirring for about 45 minutes, observing the color change to light brown. Cool to 0° C. and dropwise add diethylamine (6.00 mL, 4.242 g, 0.058) mole, keeping the temperature of the reaction below 26° C. Continue stirring for about 30 minutes once the addition is complete. Dilute to 150 mL with additional methylene chloride. Wash the methylene chloride layer with water, separate, and extract twice with 100 mL 5% sodium bicarbonate. Separate, wash again with brine , separate and dry over MgSO4. Filter through celite and condense on a rotary evaporator to a light brown, viscous liquid. Elute via chromatography with 30% ethyl acetate/70% hexane to give a clear viscous liquid (1.90 g). Concentrate under high vacuum to give a waxy solid of the title compound. (1.40 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:58])=[C:4]([C:8](=O)[CH2:9][CH2:10][N:11]([C@@H:23]2[C:39]3=[N:40][C:36](=[C:37]([CH3:49])[N:38]3[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:35]3[C:30](=[CH:31][C:32]([NH:50][C:51](=[O:54])[O:52][CH3:53])=[CH:33][CH:34]=3)[NH:29][C:28](=[O:55])[C@H:27]([CH3:56])[CH2:26][CH2:25][CH2:24]2)[C:12](=[O:22])[CH2:13]P(OCC)(OCC)=O)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].Cl>CO>[Cl:1][C:2]1[C:3]([F:58])=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([C@@H:23]3[C:39]4=[N:40][C:36](=[C:37]([CH3:49])[N:38]4[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[C:35]4[C:30](=[CH:31][C:32]([NH:50][C:51](=[O:54])[O:52][CH3:53])=[CH:33][CH:34]=4)[NH:29][C:28](=[O:55])[C@H:27]([CH3:56])[CH2:26][CH2:25][CH2:24]3)[C:12](=[O:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(CC(=O)N(CCC(=O)c1cccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2nc1n(COCC[Si](C)(C)C)c2C)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N1CCC(c3cccc(Cl)c3F)=CC1=O)c1nc-2c(C)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a round bottom flask was added 151D (35 mg, 0.040 mmol) and MeOH (2 mL). The reaction was cooled to 0° C. and sodium methoxide (26.2 mg, 0.121 mmol) was added to the reaction. The reaction was stirred at 0° C. for 10 min. Then the reaction was quenched by 1N HCl (0.081 mL, 0.081 mmol). The reaction was then partitioned between EtOAc (25 mL) and NaHCO3 (10 mL). The organic layer was separated, washed with saturated NaCl solution (10 mL), dried over MgSO4, filtered and concentrated to give methyl 151E (22 mg, 0.031 mmol, 76% yield) as a white solid. MS (ESI) m/z: 710.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16](=[O:25])[N:17]([CH3:24])[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16](=[O:25])[N:17]([CH3:24])[CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 85.5 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (4.74 g, 23.3 mmol), methyl-piperidin-4-yl-carbamic acid tert-butyl ester (5 g, 23.3 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. Upon completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was recrystallized from methanol and water to give methyl (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-carbamic acid tert-butyl ester (6.7 g, 85.5%) as brown crystals. LCMS calcd for C16H24N4O4 (m/e) 336, obsd 337 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>>[CH2:12]([NH:15][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([Br:1])=[CH:3][N:4]=2)[N:7]=1)[CH:13]=[CH2:14]
Reactant: C=CCN
Reactant: Clc1ccc2ncc(Br)n2n1
Product: C=CCNc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (1000 mg, 4.32 mmol) and allylamine (6.0 mL, 80 mmol) was heated at 80° C. (sealed tube) for 6 h. The resulting mixture was cooled to room temperature and purified on silica gel (eluting with ethyl acetate) to afford N-allyl-3-bromoimidazo[1,2-b]pyridazin-6-amine (550 mg, 51% yield) as a yellow solid: LRMS (ESI) m/z 253.0, 255.0 [(M+H)+, calcd for C9H9BrN4 252.0]
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[NH2:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1>>[N:1]1[N:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]2=[N:3][C:2]=1[NH:14][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1nc2ccc3ccccc3n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2ccc3ccccc3n2n1)c1cccnc1
Yield: 25.2 %

Procedure:
The title compound was prepared following procedure described for example 2, but starting from [1,2,4]triazolo[1,5-a]quinolin-2-amine ((A13), 67 mg; 0.37 mmol; 1.5 eq.) and nicotinoyl chloride hydrochloride (80 mg; 0.44 mmol; 1.2 eq.). Purification by flash chromatography on silica (DCM/MeOH, gradient from 98:2 to 95:5) gave the title compound as an orange oil (27 mg, 38%). HPLC, Rt: 1.83 min. (purity 97.9%). LC/MS, M+(ESI): 290.0, M−(ESI): 288.0.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22]CC)=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:28]=1.[OH-].[Na+]>C(O)C>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([OH:22])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:28]=1
Reactant: CCOC(=O)c1cccc(N2C[C@@H]3CCCN3c3nc(SC)ncc3C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)O)c1)C2=O
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Ethyl (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoate (1.85 g, 4.64 mmol) obtained in Step 1 of Example 18 was dissolved in ethanol (23 mL), and the mixture was stirred at 90° C. for 1 hour after adding a 10% aqueous sodium hydroxide solution (1.7 mL, 46.4 mL). After concentrating the mixture under reduced pressure, a 10% aqueous hydrochloric acid solution was added and stirred. The precipitated solid was filtered off and dried to give (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic acid (1.36 g, 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:11][CH2:12][C@H:13]2[CH2:15][O:14]2)=[C:6](CC=O)[CH:7]=1.C1C=C(Cl)C=[C:19]([C:24]([O:26]O)=[O:25])C=1>C(Cl)(Cl)Cl>[C:24]([O:26][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([F:16])[C:5]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)(=[O:25])[CH3:19]
Reactant: O=CCc1cc(Br)cc(F)c1OC[C@H]1CO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(Br)cc(F)c1OC[C@H]1CO1

Procedure:
Preparation according to Preparation 7 using 1-(5-bromo-3-fluoro-2-[(2R)-oxiran-2-ylmethoxyphenyl)ethanone (19.5 g, 67 mmol), CHCl3 and m-CPBA (77%, 60.5 g, 27 mmol). The mixture was heated at reflux for 24 h. The crude product was further used (Preparation 25). MS m/z (rel. intensity, 70 eV) 306 (M+, 4), 304 (M+, 4) 262 (bp), 69 (69), 57 (99).
Reaction SMILES: C(O)C.[CH2:4]([OH:13])[C@@H:5]([C@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]>>[O:12]=[CH:11][C@@H:9]([C@H:7]([C@@H:5]([CH2:4][OH:13])[OH:6])[OH:8])[OH:10]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: CCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO

Procedure:
Xylose fermentation by the constructed strains was compared in batch cultures with limited aeration. A mineral medium containing xylose (12%) and initial biomass concentration 2 g (dry weight)×L−1 were used. Results of ethanol and xylitol production by the constructed strains are shown in Table 2. Ethanol productivity of the XRm strain was 9.8 mg×(L×h)−1, which is 1.5- and 1.3-fold higher than the productivity of the XRn and the wild-type strain CBS4732, respectively. Xylitol production of these strains varied insignificantly. Ethanol productivity of the strain XRm/XDH (18.4 mg×(L×h)−1) was increased 1.5 and 2.4 times as compared to XRn/XDH and CBS4732, respectively. Strain XRm/XDH possessed 1.3- and 2.6-fold reduction in xylitol production compared with XRn/XDH and CBS4732 strains. Ethanol productivity of the strain XRm/XDH/XK (54.7 mg×(L×h)−1) was 4- and 7.4-fold higher compared to those of the strain XRn/XDH/XK (13.8 mg×(L×h)−1) and CBS4732 (7.5 mg×(L×h)−1). The xylitol production of the strain XRm/XDH/XK was significantly reduced to 0.9 mg×(L×h)−1, which is 4.7- and 3-fold lower than those of the XRn/XDH/XK and control strain, respectively. Representative fermentation profiles for the strains XRn/XDH/XK, XRm/XDH/XK and CBS4732 are shown in FIG. 3. It has to be mentioned, that the consumption of xylose by H. polymorpha strains during the fermentation is low. Ethanol produced in the initial stage of xylose fermentation is reutilized after 1-2 days of the fermentation.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:27]([NH:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:36]=[CH:37][CH:38]=[C:39]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([CH2:18][N:19]5[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:40]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=S1(=O)CCN(Cc2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(CN5CCS(=O)(=O)CC5)cc4)nn23)c1

Procedure:
N-tert-Butyl-3-{2-[4-(1,1-dioxo-1 $1(6)-thiomorpholin-4-ylmethyl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide was prepared from (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(1,1-dioxo-1$1(6)-thiomorpholin-4-ylmethyl)-phenyl]-amine and 3-t-Butylsulfamoylphenylboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow foam (90 mg, 71%). LCMS (m/e) 569 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.79 (s, 1H), 8.72 (s, 1H), 8.17 (d, 1H, J=7.9 Hz), 7.87 (d, 1H, J=7.9 Hz), 7.63-7.53 (m, 3H), 7.33 (d, 2H, J=8.3 Hz), 7.13 (s, 1H), 7.03 (d, 1H, J=4.8 Hz), 6.84 (d, 1H, J=4.8 Hz), 4.92 (s, 1H), 3.63 (s, 2H), 3.14-3.04 (m, 4H), 3.04-2.96 (m, 4H), 1.22 (s, 9H).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[NH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(#N)C>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][CH2:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:3]=2[CH3:23])([CH3:36])[CH3:37])=[CH:35][CH:34]=1)#[N:33]
Reactant: CC(C)(N)CNc1ccc(C#N)cc1
Reactant: COC(=O)c1nc(I)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1nc(NC(C)(C)CNc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 50 °C
Reaction time: 9 h
Yield: 23.1 %

Procedure:
In a bomb tube of stainless steel (Parr) fitted with an internal cylindrical glass vessel and magnetic stirrer, methyl 6-iodo-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM1, 1447 mg, 3.3 mmol), 4-(2-amino-2-methylpropylamino)benzonitrile (750 mg, 4.0 mmol), triethylamine (3.2 mL, 23 mmol) and acetonitrile (35 mL) were mixed. The mixture was purged with argon for 10 minutes. After adding bis(tributylphosphine)palladium (120 mg, 0.23 mmol), the bomb tube was sealed, evacuated and back-filled with carbon monoxide five consecutive times. The contents of the bomb tube were stirred under carbon monoxide (6.5 bar) at 50° C. for 9 h. LC-MS indicated about 50% conversion to desired product and unreacted SM. The dark red-brown solution was concentrated to dryness, dissolved in ethyl acetate (200 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated with silica to dryness. Flash chromatography on silica with ethyl acetate/n-heptane (1:3 and 1:1) as eluents gave methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (0.38 g, 22%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1N)([O-:3])=[O:2].N([O-])=O.[Na+].[I-:16].[K+]>Cl.O>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[I:16])([O-:3])=[O:2]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1I
Reaction time: 0.5 h

Procedure:
To a suspension of 2-nitro-5-chloroaniline (5.00 g) in conc. hydrochloric acid (30 ml) under cooling with ice, was added a solution of sodium nitrite (2.10 g) in water (10 ml) dropwise and the mixture was stirred for 30 minutes. Under cooling with ice, to this solution was added a solution of potassium iodide (5.30 g) in water (20 ml) dropwise and the mixture was stirred for 1 hour at room temperature. The solid that appeared was collected by filtration and was dissolved in ethyl acetate and was dried and concentrated to give a crude product of the title compound. It was purified by recrystallization from ethyl acetate-hexane to give the title compound having the following physical data (5.14 g, yellow powder).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[CH:16][CH:17]=1
Reactant: [H][H]
Reactant: O=C(O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
A suspension of 15 g. finely powdered 4-nitrobenzoyl-β-alanine in 200 ml. ethanol was stirred in an atmosphere of hydrogen in the presence of 1 g. of palladium-charcoal (5%), while cooling gently. When the absorption of hydrogen had ceased, the reaction mixture was filtered and the filtrate concentrated to a small volume. Upon adding diethyl ether and cooling, 4-aminobenzoyl-β-alanine was obtained. The yield was 11.5 g.; m.p. 156°-158° C.