Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH2:22]([N:24]1[CH2:30][CH2:29][C:28]2[CH:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:27]=2[CH2:26][CH2:25]1)[CH3:23].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)=[N:7][C:2]([NH:35][C:32]2[CH:33]=[CH:34][C:27]3[CH2:26][CH2:25][N:24]([CH2:22][CH3:23])[CH2:30][CH2:29][C:28]=3[CH:31]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: Clc1ncc(Cl)c(Nc2cccc(N3CCOCC3)c2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(N5CCOCC5)c4)n3)cc2CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(3-morpholin-4-yl-phenyl)-amine (96 mg, 0.29 mmol) was added into a vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (52 mg, 0.27 mmol) in 2-Methoxyethanol (2.7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.10 mL) was added and the reaction was heated at 120° C. After 6 h, the reaction was cooled and Macroporous carbonate resin (3.16 mmol/g loading; 400 mg, 1.25 mmol) was added and the reaction was stirred overnight, then was concentrated in vacuo onto Celite, and chromatographed (24 g alumina column, EtOAC-5% MeOH:EtOAC-5% MeOH:DCM). 5-Chloro-N*2*-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo-[d]azepin-7-yl)-N*4*-(3-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine was isolated as a yellow foam (64 mg, 49%). LCMS (m/e) 479 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.47 (m, 2H), 7.37 (d, 1H, J=2.0 Hz), 7.14 (dd, 1H, J=2.3, 8.1 Hz), 6.96 (d, 1H, J=7.9 Hz), 6.92 (m, 3H), 6.82 (s, 1H), 3.89 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz), 2.85 (m, 4H), 2.63 (m, 4H), 2.57 (q, 2H, J=7 Hz), 1.10 (t, 1H, J=7 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[NH:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:17]2[NH:16][C:15](=[O:27])[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:20][CH2:19][C:18]=2[CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2

Procedure:
A mixture of 21.6 g (59.2 mmol) 3-(1-benzylpiperidin-4-yl)-7-methoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 2.5 g palladium on charcoal (10%) in 300 mL methanol was hydrogenated in a 3 bar hydrogen atmosphere at 50° C. until the reaction was complete. The catalyst was removed by suction filtering and the mother liquor concentrated by rotary evaporation. The residue was triturated with 150 mL DIPE, suction filtered, washed with 100 mL DIPE and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][NH:21][CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][N:21]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1
Reactant: CC1(c2ccccc2)CCC(=O)C2CNCC21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 1.66 g of 2-methoxyphenylacetic acid in 40 cm3 of dichloromethane are added, at 4° C., 1.62 g of N,N'-carbonyldiimidazole. Stirring for 30 minutes at room temperature is followed by dropwise addition of a solution containing 1.85 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-4-perhydroisoindolone hydrochloride and 0.7 g of triethylamine in 30 cm3 of dichloromethane. After stirring for 2 hours, the reaction mixture is washed twice with 50 cm3 of water and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 50 cm3 fractions. Fractions 16 to 60 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is crystallized in 30 cm3 of ethyl acetate. 1.3 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone are obtained, in the form of white crystals melting at 160° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]#[N:15])=[N:12][CH:13]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]([NH2:15])=[O:26])=[N:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A flask was charged with 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (35.19 g, 88.1 mmol), and sulfuric acid (227.3 g, 2317 mmol) and stirred at ambient temperature overnight. Water (100 mL) was slowly added to the reaction which was cooled in an ice bath, then ice (150 g) was added. 40% NaOH was slowly added until the pH was about 12. The mixture was extracted ethyl acetate (750 mL×2), and dichloromethane (500 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (27.69 g, 77.9 mmol, 89% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+:14]([O-])([O-:16])=[O:15].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
To a solution of 1-chloro-4-(isopropylsulfonyl)benzene (Step B, 679 mg, 3.1 mmol) in sulfuric acid (3 mL) was added potassium nitrate (555 mg, 5.5 mmol) at 80° C. The mixture was stirred at 90° C. for 2 h. Ice water (5 mL) was added, and the mixture was extracted with ethyl acetate (25 mL) and washed with water (10 mL×2) and brine (10 mL). The organic extracts were dried over sodium sulfate and concentrated to afford the title compound (849 mg, containing ethyl acetate) as a white solid.
Reaction SMILES: O=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(OC(OCC)OCC)C>CCO>[O:25]1[CH2:24][CH2:23][CH:22]([N:3]2[CH:2]=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:11]2[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=24)=[N:7][CH:8]=3)[CH2:27][CH2:26]1
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: N#Cc1ccn2ncc(-c3ncc4ncn(C5CCOCC5)c4n3)c2c1
Temperature: 123 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of the compound obtained in example 1 section d (100 mg, 0.30 mmol) in EtOH (1 mL), PTSA monohydrate (5.7 mg, 0.03 mmol) and triethylorthoformate (1 mL) were added. The reaction mixture was heated in a CEM Explorer microwave oven at 123° C. and 270 W for 30 min. Then, it was evaporated to dryness. The crude product thus obtained was chromatographed over silica gel using MeOH/EtOAc mixtures of increasing polarity as eluent, to afford 81 mg of the desired compound (79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=O)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.Cl.[NH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH:28]=[N:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: O=Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: NN1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(COc2ccc(Nc3ncnc4ccc(C=NN5CCCC5)cc34)cc2Cl)c1
Yield: 81.4 %

Procedure:
In a mixture of 1 mL of tetrahydrofuran and 0.1 mL of water were dissolved 40 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino) 6-formylquinazoline (IV-1) and 13 mg of 1-amino-pyrrolidine hydrochloride, followed by a reaction at room temperature overnight. After the reaction, aqueous saturated sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dehydrated by passing through Presep (registered trademark), and the filtrate was concentrated. The concentrated residue was purified by chromatography (eluting with hexane:ethyl acetate-2:1→1:1) using an amino column to obtain 38 mg of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(pyrrolidin-1-yliminomethyl)quinazoline (IX-1) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.CN(C=O)C.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])=[CH:32][CH:31]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(Br)c2c(N)ncnn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
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: COCCOC
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)c2c(N)ncnn12
Temperature: 80 °C
Yield: 26.3 %

Procedure:
A mixture of butyl 4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (456.0 mg, 1.46 mmol), {4-[(tert-butoxycarbonyl)amino]phenyl}boronic acid (517.8 mg, 2.18 mmol), 2 M aqueous sodium carbonate solution (2.2 mL, 4.40 mmol), and tetrakis(triphenylphosphine)palladium(0) (168.3 mg, 0.15 mmol) in 1,2-dimethoxyethane (11 mL) was heated (80° C.) overnight. The reaction mixture was diluted with DMF and purified by HPLC using a gradient of 30-95% of MeCN in water to give 163.2 mg (26%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.52 (s, 1 H), 8.08 (bs, 1 H), 8.06 (s, 1 H), 7.56 (d, J=8.6 Hz, 2 H), 7.35 (d, J=8.6 Hz, 2 H), 7.18 (s, 1 H), 5.67 (bs, 1 H), 4.25 (t, J=6.5 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.37 (m, 2 H), 0.93 (t, J=7.4, 3 H); MS [M+H]+=426.2; LCMS RT=3.43 min.
Reaction SMILES: [CH2:1](I)[CH3:2].[Br:4][C:5]1[C:10]([F:11])=[CH:9][N:8]=[C:7]([OH:12])[CH:6]=1>C(Cl)Cl>[Br:4][C:5]1[C:10]([F:11])=[CH:9][N:8]=[C:7]([O:12][CH2:1][CH3:2])[CH:6]=1
Reactant: Oc1cc(Br)c(F)cn1
Reactant: CCI
Solvent: ClCCl
Product: CCOc1cc(Br)c(F)cn1
Temperature: 25 °C

Procedure:
2.08 mL (26.0 mmol) Ethyliodide and 1.08 g (3.91 mmol) Ag2CO3 are added to a mixture of 500 mg (2.160 mmol) 4-bromo-5-fluoro-pyridin-2-ol in 10 mL DCM. The mixture is stirred at r.t. over night. Then the reaction mixture is quenched by the addition of water and DCM. After filtration the org. layer is separated, dried with Na2SO4 and the solvent is removed in vacuo.
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:8]=1)[CH:2]=[CH2:3].[OH2:25]>Cl.Cl.[Cl-].[Cl-].[Zn+2].[Cl-].[Zn+2].[Cl-]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][N:4]2[C:1]3[C:21](=[CH:22][CH:23]=[CH:3][CH:2]=3)[CH2:20][CH:19]2[CH3:24])=[O:25])=[CH:8][C:9]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Reactant: O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 6 h

Procedure:
In a 50 ml round bottom was placed 8 grams of Lucas reagent. The reagent is prepared by dissolving 16 grams of anhydrous zinc chloride in 10 ml of concentrated hydrochloric acid. To this reagent was added 100 mg (0.27 mmols) of 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine with stirring under nitrogen for a short time to dissolve the solid. The reaction cyclized at 60° C. over 6 hours. The reactant was worked up by pouring the cooled reaction mixture into water and extracting the product into ethyl acetate. The ethyl acetate phase was cross washed several times with water and sodium bicarbonate solution. The ethyl acetate solution is dried with magnesium sulfate, clarified and evaporated to dryness yielding 84 mg of crude 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:25]=[C:26]([C:30]2[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=2)[CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[C:35]1([N:34]2[C:33]3[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=3[N:31]=[C:30]2[C:26]2[CH:25]=[C:24]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([N:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:15]=3)[CH:29]=[N:28][CH:27]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Reactant: OB(O)c1cncc(-n2c3ccccc3c3ccccc32)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: C1COCCO1
Solvent: O
Product: c1ccc(-n2c(-c3cncc(-c4cncc(-n5c6ccccc6c6ccccc65)c4)c3)nc3ccccc32)cc1
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of (5-(9H-carbazol-9-yl)pyridin-3-yl)boronic acid (2C) (0.90 g, 3.1 mmol), 2-(5-bromopyridin-3-yl)-1-phenyl-1H-benzo[d]imidazole (1F) (0.856 g, 3.1 mmol), Pd(PPh3)4 (0.18 g, 0.155 mmol) and potassium carbonate (1.07 g, 7.8 mmol) in dioxane/water (20 mL/5 mL) was degassed and heated at about 90° C. overnight under argon atmosphere. The whole was poured into ethyl acetate (100 mL), then washed with brine (50 mL). The organic phase was collected and dried over Na2SO4, absorbed on silica gel, then purified by flash column (dichloromethane/methanol 40:1) to give a light yellow solid (0.78 g), which was purified again by flash column (silica gel, dichloromethane/methanol 50:1) followed by recrystallization in dichloromethane/methanol to give HTH-2, a light yellow solid (0.60 g, 38% yield).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15]CC3C=CC=CC=3)[C:11]=2[C:23]#[N:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([OH:32])C=CC=CC=1>S(=O)(=O)(O)O>[C:1]1([O:7][C:8](=[O:25])[NH:9][C:10]2[S:14][N:13]=[C:12]([OH:15])[C:11]=2[C:23](=[O:32])[NH2:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1c(OCc2ccccc2)nsc1NC(=O)Oc1ccccc1
Agent: O=S(=O)(O)O
Product: NC(=O)c1c(O)nsc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The wet solid, (3-Benzyloxy-4-cyano-isothiazol-5-yl)-carbamic acid phenyl ester, (320 g) was added slowly to concentrated sulfuric acid (650 mL) over 1.5 hours. Additional concentrated sulfuric acid (100 mL) was added and the mixture stirred a further 3 hours. The viscous solution was diluted by slow addition of ice (2000 g) followed by vigorous stirring for an additional 2 hours. The acid was partially removed by dividing the suspension into eight containers that were placed in a centrifuge, spun at 3000 rpm for 45 minutes at 21° C. The aqueous layer was discarded, additional pure water was added, the pellet resuspended, and the process repeated. After seven dilution/centrifugation/redilution cycles, the pH of the aqueous layer had increased to ˜4 and the solid was collected and dried by drawing air through a cake in a funnel for 2 days. The less-wet solid was crushed, placed again in the filter, and air was again drawn through the solid for another day. This process was repeated until the solid was dry to afford a tan solid (234 g, 105% over two steps, minor impurities present—did not interfere appreciably with the subsequent steps). 1H NMR (400 MHz, DMSO) δ 7.00 (broad s, 1H), 7.27-7.31 (m, 3H), 7.40-7.45 (m, 2H), 7.89 (s, 1H), 8.08 (s, 1H), 11.92 (s, 1H); MS (APCl, m/z): 184 [M-(H and PhOH)]−.
Reaction SMILES: [CH:1]1([N:5]2[C:9]([C:10](O)=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH:1]1([N:5]2[C:9]([C:10]([Cl:16])=[O:11])=[CH:8][C:7]([CH3:13])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)n(C2CCC2)n1
Solvent: c1ccccc1
Product: Cc1cc(C(=O)Cl)n(C2CCC2)n1
Yield: 96.1 %

Procedure:
To 3.02 g of 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylic acid were added 60 ml of benzene and 10 ml of thionyl chloride. The mixture was refluxed for two hours. Then the solvent was distilled off under reduced pressure and thus 3.2 g of 1-cyclobutyl-3-methyl-1H-pyrazole-5-carboxylic acid chloride was obtained (yield: 96.1%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1C([N+]([O-])=O)=CC=C([O:16][P:17](O)([OH:19])=[O:18])C=1.C(O)C>C(OC)(C)(C)C>[P:17]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])([OH:19])([OH:18])=[O:16]
Reactant: OCC(O)CO
Reactant: O=[N+]([O-])c1ccc(OP(=O)(O)O)cc1
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=P(O)(O)OCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Glycerol (10 mmol; 0.92 g) is adsorbed to an approximately equal amount of silica gel (1.0 g) and then suspended in 20 ml of t-BuOMe. To this mixture is added p-nitrophenylphosphate (10 mmol) followed by acid phosphatase from potato (1000 U; 200 mg). The mixture is stirred at room temperature for 24 hours. The solvent is removed by vacuum, the residue is thoroughly extracted with water (3×150 ml), and all solids are removed by filtration. The resulting aqueous solution is concentrated under vacuum to 75 ml and treated with a solution 21 mmol of BaCl2.2H2O to form a precipitate. To the suspension is added 500 ml of 95% ethanol and the precipitate is allowed to settle overnight. The. suspension is filtered and the solid material is dried over CaSO4. Glycerol-1-phosphate (8.5 mmol) is obtained containing 94% of the title compound as the barium salt.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([Cl:20])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
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: C1COCCO1
Product: COc1ccc(-c2ccc3nc(N)nc(N)c3n2)cc1Cl
Yield: 38.7 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (464 mg, 2.37 mmole), K2CO3 (1332 mg, 9.64 mmole), 3-chloro-4-methoxyphenyl boronic acid (907 mg, 4.86 mmole) in 1,4-dioxane (35.5 ml) and water (7 ml) was purged with a stream of nitrogen for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.24 mmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 4 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel flash chromatography, using methanol and 1% Et3N in CH2Cl2 as eluent, gradually increasing the methanol concentrations from 5% to 10%, to afford the pure title compound (277 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 302 ([M+H]+, 100).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[Li]CCCC.[C:15](Cl)(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].[Na+].[Cl-]>C1COCC1.CCCCCC>[C:15]([N:5]1[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][O:7][C:6]1=[O:9])(=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CCCCCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2.08 g (16.10 mmol, 1 equivalent) of (4S)-4-isopropyl-oxazolidin-2-one in 15 ml of THF is cooled to -78° C. and mixed drop by drop with 11.6 ml (18.52 mmol, 1.15 equivalents) of a 1.6 M solution of n-BuLi solution in hexane. Then, a solution of 2.95 g (20.13 mmol, 1.25 equivalents) of hept-6-enoyl chloride in 10 ml of THF is added at -78° C. It is allowed to heat to room temperature, and the reaction solution is poured onto saturated NaCl solution. The aqueous phase is extracted with ether, the combined organic phases are dried on MgSO4, and the solvent is distilled off in a rotary evaporator. The residue is purified by column chromatography with PE:DE=3:1. 3.55 g (14.82 mmol, 92%) of oxazolidinone 21 is obtained as a colorless oil.