Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.[OH-].[Na+]>ClC1C=CC=CC=1>[CH:10]1([NH:13][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH2:12][CH2:11]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: Clc1nc(Cl)nc(NC2CC2)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
133 g of cyanuric chloride are suspended in 720 ml of chlorobenzene and cooled to -10° C. To this suspension are added with stirring 50 ml of cyclopropylamine dropwise over a period of 25 minutes. Keeping the temperature at -10° C., 96 ml of aqueous sodium hydroxide (30% NaOH) are added dropwise. The reaction mixture is then stirred at -10° C. for 11/2 hours and allowed to stand for a further 16 hours at room temperature, after which it is washed with water (2×400 ml), dried over anhydrous sodium sulphate and filtered. The excess chlorobenzene is then removed by water jet vacuum distillation. 138 g of 2-cyclopropylamino-4,6-dichloro-s-triazine in the form of white crystals are obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:31]=[C:7]3[NH:8][C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([C:4]2[N:31]=[C:7]3[N:8]([CH3:34])[C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C3CC3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.4 %

Procedure:
A mixture of 4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.18 g), methyl iodide (0.033 mL), potassium carbonate (0.12 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C@@H:27]2[CH2:32][CH2:31][CH2:30][C@H:29]([NH2:33])[CH2:28]2)[CH:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:33][C@H:29]2[CH2:30][CH2:31][CH2:32][C@@H:27]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:28]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CCC[C@@H](c2cccnc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N[C@H]3CCC[C@@H](c4cccnc4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 93 °C
Reaction time: 9 h
Yield: 13.4 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (457 mg, 1.65 mmol), cis-3-(3-pyridyl)cyclohexylamine (348 mg, 1.97 mmol) and diisopropylethylamine (0.63 mL, 3.63 mmol) in anhydrous DMSO (8 mL) was stirred at 93° C. for 9 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[cis-3-(3-pyridyl)cyclohexylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (96.0 mg, 13%) as a yellow powder.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>CCO>[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7]
Reactant: COC(=O)C(C)(C)CN
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Solvent: CCO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Yield: 64.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.14 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-amino-2,2-dimethyl-propionic acid methyl ester (90 mg, 0.70 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 3 h. The solvent was evaporated, and the residue was purified by column chromatography (0-30% EtOAc/hexanes) to give 38 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ ppm=13.9 (s, 1H), 8.20-8.40 (m, 2H), 7.10-7.70 (m, 7H), 3.79 (s, 3H), 3.62 (d, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: N#N.[O:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH3:8])[CH3:5].C[CH:11]([CH2:13][C:14]([CH3:16])=[O:15])[CH3:12]>OS(O)(=O)=O>[OH:15][CH:14]([CH2:13][CH2:11][CH3:12])[CH2:16][C:4](=[O:3])[CH3:5].[CH3:5][C:4](=[O:3])[CH2:6][C:7]([CH3:9])([OH:15])[CH3:8]
Reactant: CC(=O)CC(C)C
Reactant: CC(=O)C=C(C)C
Agent: N#N
Agent: O=S(=O)(O)O
Product: CC(=O)CC(C)(C)O
Product: CCCC(O)CC(C)=O

Procedure:
A 150 ml jacketed glass reactor was equipped with a thermocouple, magnetic stirrer, feed and sample ports, and an overhead condenser. The reactor was maintained under positive N2 atmosphere by connecting the condenser vent line to a N2 bubbler. Fifty ml (46.5 grams) of mesityl oxide heavy ends from the current MIBK process (the reaction medium for the dehydration reaction step), which contained the H2SO4 catalyst, was added to the reactor.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:27])([CH3:26])[C:9]([NH:11][C:12]1[C:20]([O:21][CH3:22])=[C:19]([F:23])[C:18]([I:24])=[C:17]([CH3:25])[C:13]=1[C:14]([NH2:16])=O)=[O:10].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:14]([C:13]1[C:17]([CH3:25])=[C:18]([I:24])[C:19]([F:23])=[C:20]([O:21][CH3:22])[C:12]=1[NH:11][C:9](=[O:10])[C:8]([CH3:26])([CH3:7])[CH3:27])#[N:16]
Reactant: COc1c(F)c(I)c(C)c(C(N)=O)c1NC(=O)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 939 %

Procedure:
4-Dimethylaminopyridine (149 mg, 1.22 mmol) was added to a pyridine (100 ml) suspension of 2-(2,2-dimethylpropionylamino)-4-fluoro-5-iodo-3-methoxy-6-methylbenzamide (I-68) (4.97 g, 1.22 mmol), and cooled at 0° C. Trifluoromethanesulfonic acid anhydride (6.17 ml, 36.5 mmol) was dropwise added to it, followed by stirring at room temperature for 1 hour, then ethyl acetate (400 ml) was put thereinto. The organic layer was washed with 1 N hydrochloric acid (300 ml×5), saturated brine (300 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1) to obtain the entitled compound (4.47 g, 94%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.C(OCC)(=O)C.[H][H]>C(O)C>[CH3:12][C:2]([O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]1
Reactant: CC(C)(Cn1ccc([N+](=O)[O-])n1)OC[C@H]1CO1
Reactant: [H][H]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Yield: 103.1 %

Procedure:
A mixture of 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.3 g, 1.24 mmol), and ethyl acetate (15 mL), ethanol (15 mL) was subjected to the H-Cube (Thales Nano) at 1 mL/min at 10° C., 10 psi hydrogen. The first time through not completely reduced. Resubjected and complete reduction of nitro group by NMR. Solvent was removed under reduced pressure to afford 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine as an oil (0.27 g, 100%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][C@@H:2]1[CH2:15][OH:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][C@H:2]2[CH2:3][CH2:4][C:5]3[C:10](=[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]4=[CH:7][CH:6]=3)[O:1]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: OC[C@H]1CCc2ccc3ccccc3c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3ccc4ccccc4c3O2)cc1
Temperature: 50 °C
Yield: 77.2 %

Procedure:
To a solution of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethanol (0.90 g, 4.22 mmol) in dichloromethane (50 mL) is added p-toluenesulfonyl chloride (1.61 g, 8.44 mmol), 4-(dimethylamino)pyridine (0.10 g, 0.84 mmol), and N,N-diisopropylethylamine (1.20 g, 9.28 mmol) and the reaction mixture is heated to 50° C. for 12 h. The reaction mixture is quenched by the addition of water (100 mL). The aqueous layer is separated and extracted with dichloromethane (100 mL). The combined organic extracts are washed with aqueous hydrogen chloride (1.0 M, 100 mL), water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate), and the solvent is removed in vacuo to provide a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:3) provides 1.20 g (77%, 50% ee) of (2R)-3,4-dihydro-2H-benzo[h]chromen-2-ylmethyl 4-methylbenzenesulfonate as a white solid. [α]D25=−10.23 (c 10.16 in chloroform, 50% ee); Rf=0.68 (silica, ethyl acetate:hexanes 2:3); mp 107-111° C.; Anal. Calcd. for C21H20O4S: C, 68.46; H, 5.47. Found: C, 68.10; H, 5.27.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:18].[F:19][C:20]1[CH:21]=[C:22]([OH:35])[CH:23]=[CH:24][C:25]=1B1OC(C)(C)C(C)(C)O1.CCOCC>O.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:21]=[C:22]([OH:35])[CH:23]=[CH:24][C:25]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:18]
Reactant: CC1(C)OB(c2ccc(O)cc2F)OC1(C)C
Reactant: OCCCc1ccc(-c2ccc(Br)c(F)c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCCCc1ccc(-c2ccc(-c3ccc(O)cc3F)c(F)c2)cc1

Procedure:
16.5 g (59 mmol) of sodium metaborate octahydrate and 1.3 g (1.8 mmol) of bis(triphenylphosphine)palladium(II) chloride are initially introduced in 150 ml of water and 50 ml of THF, 12.5 g (38.5 mmol) of 3-(4′-bromo-3′-fluorobiphenyl-4-yl)propan-1-ol are added, and a solution of 12.5 g (0.053 mol) of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol in 50 ml of THF is subsequently added dropwise. The batch is heated under reflux overnight, taken up in MTB ether and washed three times with water. The org. phase is dried over sodium sulfate, the solvent is removed in vacuo, and the crude product is recrystallised from toluene/ethyl acetate (9:1), giving 2,2′-difluoro-4″-(3-hydroxypropyl)[1,1′;4′,1″]-terphenyl-4-ol as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:14]=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2S(C1C=CC=CC=1)(=O)=O.N1C=CC=CC=1.[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=1>C(Cl)Cl>[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[O:44])[N:42]=1
Reactant: CS(=O)(=O)Nc1cncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)c1
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(NS(C)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
N-{5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (50 mg) was dissolved in DCM (1 ml) and pyridine (0.014 ml) was added. A solution of 2-methyl-1,3-thiazole-4-carbonyl chloride (22 mg) in DCM (1 ml) was added to the reaction and the mixture was stirred at RT for 30 min. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (10 mg) was added to the reaction and stirring continued for 30 min. Further 2-methyl-1,3-thiazole-4-carbonyl chloride (40 mg) was added then the reaction was quenched with water and passed through a hydrophobic frit. The organic layer was evaporated to dryness and the residue was dissolved in DMSO:MeOH (1 ml, 1:1, v/v) and purified by MDAP (method E). The compound was dissolved in MeOH containing a few drops of 2M NaOH and stirred for 5 mins at RT. The residue was dissolved in MeOH and loaded onto an SAX SPE cartridge pre-conditioned with MeOH. After eluting with MeOH and evaporating to dryness, the residue was dissolved in DMSO and purified by MDAP (method E) to give the title compound (9 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1.[CH2:25]([N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][C:29]1=[O:38])[C:26]#[CH:27].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:27]#[C:26][CH2:25][N:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:29]3=[O:38])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([OH:24])[N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2O
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)CCc4ccccc43)cc1C(c1ccccc1F)=NC2O

Procedure:
The title compound was obtained by reacting rac-6-(2-fluorophenyl)-4-hydroxy-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined good fractions were evaporated and the residue was crystallized from methanol/ethyl acetate to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-hydroxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 253°-255° with decomposition. These crystals contained molar equivalents of water.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][NH2:21]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH3:20])[N:7]=3)=[CH:12][NH:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: CN
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Product: CNc1nccc(-c2c[nH]nc2-c2ccc(F)cc2)n1
Temperature: 100 °C

Procedure:
A suspension of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 (0.3 g, 0.0011 mol) in 10 mL of methylamine (40% water solution) was heated in a sealed tube at 100° C. overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried to give 0.2 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine, as a white solid (68% yield), mp: 217-218° C.; Anal Calc'd for C14H12FN5: C, 62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N, 25.90.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1.[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)[CH:19]=[CH2:18]
Reactant: O[C@@H]1CCC[C@H](OCc2ccccc2)C1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, 12 g of sodium hydride (55-65%) are initially charged in 200 ml of abs. DMF, and the mixture is stirred at RT for 10 min. With ice-cooling, 54 g of benzyl (1S,3R)-3-hydroxycyclohex-1-yl ether in 70 ml of DMF are added dropwise. The mixture is stirred at RT for 90 min. With ice-cooling, 50 g of allyl bromide are slowly added dropwise. After the addition has ended, the mixture is stirred at 45° C. for 1 h. According to TLC, the reaction is complete. The reaction solution is quenched with 15 ml of iPrOH, diluted with water and sat. NaCl solution and extracted with MTBE. The combined organic phases are washed with water and NaCI solution, dried over MgSO4 and concentrated. This gives 60 g of benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether as a light-beige oil. C16H22O2 (246.35), MS (ESI): 247 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8].CO.O.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1cccc(F)c1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of ethyl 3-fluorophenoxy-acetate (2 g, 10 mmol) in 24 mL of a 1:1:1 solution of MeOH:H2O:THF is added lithium hydroxide monohydrate (2.25 g, 54 mmol). The solution is stirred for 16 hours. After this time, the solution is concentrated under reduced pressure to ⅓ of its volume. The remaining solution is acidified to pH=3 with 1N HCl (aq.). The aqueous solution is extracted with EtOAc. The organic layer is washed with a saturated solution NaCl (aq.). The organic layer is dried over MgSO4, filtered and concentrated to give the product (1.65 g, 9.7 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ9.8 (bs, 1H), 7.28 (m, 1H), 6.69 (m, 3H), 4.70 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N+:15]([O-:18])(O)=[O:16].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([C:11]=1[N+:15]([O-:18])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:21])[CH3:20]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc2ccccc2cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1c(C(=O)O)cc2ccccc2c1[N+](=O)[O-]
Reaction time: 168 h

Procedure:
A solution of 5 g of 3-amino-2-naphthalenecarboxylic acid in 40 ml of acetic anhydride is stirred at ambient temperature for 30 minutes and then 5 ml of nitric acid are added dropwise. The reaction mixture is then stirred in an ice bath for 7 days and is then poured onto ice. The precipitate formed is filtered off, washed with water and then dried and rinsed with 40 ml of methanol, allowing the expected product to be isolated after drying.
Reaction SMILES: O[CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8].[ClH:23].O.C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C>[Cl:23][CH:2]([C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)[CH:3]([CH3:9])[CH2:4][O:5][CH2:6][CH2:7][OH:8]
Reactant: CC(COCCO)C(O)c1ccc(Cc2cccnc2)cc1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(COCCO)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 98 %

Procedure:
In 13.7 ml of ethanol was dissolved 2.74 g of 3-[p-[1-hydroxy-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine, and the resulting solution was saturated with hydrogen chloride with ice-cooling, after which the solution was subjected to reaction at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 10 ml of water and 20 ml of ethyl acetate, after which the pH of the resulting mixture was adjusted to 7.0 with sodium hydrogencarbonate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 2.85 g (yield 98%) of colorless, oily 3-[p-[1-chloro-3-(2-hydroxyethyl)oxy-2-methylpropyl]benzyl]pyridine.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:23]=[CH:22][C:15]3[N:16]=[C:17](S(C)=O)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].Cl.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[OH:32].C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[OH:32][C@H:27]1[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]1[NH:25][C:17]1[S:18][C:14]2[CH:13]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=3)[CH:23]=[CH:22][C:15]=2[N:16]=1
Reactant: N[C@H]1CCCC[C@@H]1O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCC[C@@H]4O)sc3c2)ccn1
Temperature: 110 °C

Procedure:
To the solution of 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (70 mg, 0.202 mmol, 1.0 eq) in DMA (600 μL), was added (1S,2S)-2-aminocyclohexanol hydrochloride (92 mg, 0.606 mmol, 3.0 eq) followed by diisopropylethylamine (0.21 mL, 1.21 mmol). The reaction was heated at 110° C. for 24-hours. The neat reaction mixture was purified on reverse phase preparatory HPLC. Pure fractions were lyophilized as TFA salts. M+H=398
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][CH2:8][CH2:9][S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.CC(O)=O>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C:4]([NH:7][CH2:8][CH2:9][S:10][C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5]
Reactant: O=C(Cl)CCBr
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CCBr)NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromopropionylchloride (62.5 μl, 0.62 mmol) was dissolved in 0.5 ml CH2Cl2 and added to a solution of H2N—CH2—CH2-STrt (200 mg, 0.56 mmol), DIEA (196 μl, 1.1 mmol) in CH2Cl2 (1 ml). The mixture was stirred for 1 h at RT. The reaction mixture was acidified with AcOH (100 μl) and the solvent was removed in vacuo. The residue was purified over silica gel (heptane/EtOAc=1:1) to obtain Br—(CH2)2CONH—(CH2)2-STrt.