Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:5]([O:6]1)[CH2:4][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]3)[CH:9]=1)[CH2:2]2.F[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:5]12[CH2:7][CH:1]([O:6]1)[CH2:2][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([NH:25][C:27]4[N:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:23][CH2:24]3)[CH:9]=1)[CH2:4]2
Reactant: Fc1ncccn1
Reactant: NC1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(NC2CCC(Oc3cc(N4CC5CC(C4)O5)cc4nccnc34)CC2)nc1
Temperature: 150 °C
Yield: 51.5 %

Procedure:
A mixture of 4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexanamine (190 mg, 0.5581 mmol), 2-fluoropyrimidine (60 mg, 0.6118 mmol) and DIEA (200 μL, 1.148 mmol) in 2-propanol (2 mL) was heated in a microwave reactor for 20 min at 150° C. The reaction mixture was concentrated, and then purified from 12 g silica gel cartridge with 0-6% MeOH/DCM to yield N-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]pyrimidin-2-amine (120.2 mg, 48.9%) as a yellow solid. Mass+1: 419.23; Retention Time: 0.72; NMR Annotation: 1H NMR (400 MHz, Chloroform-d) δ 8.42 (d, J=1.9 Hz, 1H), 8.30 (d, J=1.9 Hz, 1H), 8.04 (d, J=4.8 Hz, 2H), 6.65-6.56 (m, 2H), 6.28 (t, J=4.8 Hz, 1H), 4.99 (d, J=8.1 Hz, 1H), 4.60 (d, J=6.5 Hz, 3H), 3.79 (dd, J=8.2, 4.0 Hz, 0H), 3.62-3.38 (m, 4H), 3.17-3.03 (m, 1H), 2.07-1.90 (m, 2H), 1.89-1.59 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8](=S)[NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[Cl:17])=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:22]O>O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[N:9]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[Cl:17])[O:11][N:22]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(NC(=S)OCc1ccc(Cl)cc1)c1sccc1Cl
Agent: Cl
Solvent: O
Product: Clc1ccc(COc2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A stirred solution of (3-chlorothiophene-2-carbonyl)-thiocarbamic acid O-(4-chloro-benzyl) ester (52.3 mg, 0.151 mg), hydroxylamine hydrochloride (20.7 mg, 0.298 mmol) was refluxed under argon for 1 h. The solution was cooled to room temperature, then water (6 mL) was added to precipitate the product, and the mixture was filtered. The filter cake was dissolved in dichloromethane, filtered through glass wool, and rotary evaporated to dryness. The product was recrystallized from dichloromethane/methanol to yield 3.1 mg (6.2%) of the title compound as a white solid. 1H NMR (CDCl3): 7.58 (d, J=5.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.10 (d, J=5.1 Hz, 1H), 5.36 (s, 2H).
Reaction SMILES: C1COCC1.C([O:9][C:10]12[CH2:14][C:12]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13]1)[CH2:11]2)(=O)C.[OH-].[Na+]>CO>[OH:9][C:10]12[CH2:14][C:12]([NH:15][C:16](=[O:18])[CH3:17])([CH2:13]1)[CH2:11]2
Reactant: CC(=O)NC12CC(OC(C)=O)(C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NC12CC(O)(C1)C2

Procedure:
To a THF (2 mL) solution of 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3) (1 mmol) is added methanol (0.7 mL) followed by a aqueous solution of NaOH (1.4 M, 0.7 mL, 1 eq.) at r.t. The mixture is stirred and monitored by TLC. After complete consumption of the starting material, saturated ammonium chloride is added and the mixture is stirred for 5 min. The volatiles are removed under vacuum and the resultant mixture is extracted with EtOAc (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to give compound 1.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH2:24][CH:25]([CH3:27])[CH3:26])[NH:14][C:13](=[O:28])[N:12]=3)[CH:9]=2)[NH:4][N:3]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.CN(C)C=O>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH2:29][NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[O:23][CH2:24][CH:25]([CH3:26])[CH3:27])[NH:14][C:13](=[O:28])[N:12]=4)[CH:9]=3)[NH:4][N:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)nc(=O)[nH]1
Reactant: COc1cccc(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cccc(CNc2n[nH]c3ccc(-c4cc(-c5ccccc5OCC(C)C)[nH]c(=O)n4)cc23)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
To a 50 mL round bottom flask were added commercially available 4-(3-amino-1H-indazol-5-yl)-6-(2-isobutoxyphenyl)pyrimidin-2(1H)-one (130 mg, 0.35 mmol), m-anisaldehyde (420 μL, 3.5 mmol, 10 eq), dimethylformamide (10 mL) and glacial acetic acid (10 drops). The reaction mixture was heated to 50° C. in an oil bath and stirred for 1 h. The mixture was allowed to cool before adding sodium cyanoborohydride (1M THF solution (Aldrich), 3 mL, 3 mmol) and subsequently stirred at room temperature for 1 h. Formation of product was confirmed by LC/MS and was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to yield 40 mg (98%) of the title compound: 1H-NMR (400 MHz, d6-DMSO): δ 11.78 (s, 1H), 11.64 (s, 1H), 8.73 (s, 1H), 8.06 (d, 1H), 7.60 (d, 1H), 7.46-7.54 (m, 1H), 7.28-7.34 (m, 1H), 7.15-7.26 (m, 2H), 7.06-7.12 (m, 1H), 6.96-7.01 (m, 1H), 6.73-6.81 (m, 1H), 4.42-4.48 (m, 2H), 3.82-3.88 (m, 2H), 3.72 (s, 3H), 1.94-2.07 (m, 1H), 0.90-0.95 (m, 6H). MS (EI) for C29H29N5O3: 495 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@:8]([CH3:19])([CH:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+:21].[OH-]>CCO>[NH2:21][CH2:18][CH:16]([OH:17])[C@:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:19]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C1CO1
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C(O)CN

Procedure:
A solution of tert-butyl((1R)-1-methyl-1-oxiran-2-yl-2-phenylethyl)carbamate (986 mg, 3.56 mmol) in EtOH (35 mL) and NH4OH (35 mL) was stirred at 60° C., sealed, for 16 h, concentrated in vacuo and purified by flash chromatography (silica, 0-30% (10% NH4OH/MeOH)/CH2Cl2) to provide tert-butyl ((1R)-3-amino-1-benzyl-2-hydroxy-1-methylpropyl)carbamate as a thick oil. 1H NMR (400 MHz, CD3OD, 1:1 diastereomeric mixture) δ 7.30-7.14 (m, 5H), 4.01 (br d, J=9.2 Hz, 0.5H), 3.54 (dd, J=10.0, 2 Hz, 0.5H), 3.39 (br s, 0.5H), 3.36 (br s, 0.5H), 2.94-2.56 (m, 4H), 1.47 (s, 9H), 1.03 (s, 1.5H), 0.99 (s, 1.5H).
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)(=O)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].CN(C)C(N(C)C)=N>O1CCCC1.CN(C)C=O>[O:26]=[C:21]1[N:22]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:23](=[O:25])[CH2:24][O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2C(=O)COC2=O)CC1

Procedure:
A suspension of 13.60 g (46.36 mmol) of 1,1-dimethylethyl 4-{[(methylsulphonyl)oxy]methyl}piperidine-1-carboxylate, prepared in step 2.1., 9.37 g (92.72 mmol) of 1,3-oxazolidine-2,4-dione and 16.02 g (139.08 mmol) of 1,1,3,3-tetramethylguanidine in a mixture of 180 ml of tetrahydrofuran and 30 ml of dimethylformamide is heated at reflux for 24 hours. It is allowed to return to ambient temperature and is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 98/2 then 95/5 mixture of dichloromethane and methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14](=O)[CH2:15]Br)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1.[C:21]([NH2:24])(=[S:23])[CH3:22]>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:20])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:24]=[C:21]([CH3:22])[S:23][CH:15]=3)=[CH:12][CH:11]=[C:10]([O:18][CH3:19])[C:8]=2[N:9]=1
Reactant: CC(N)=S
Reactant: COC(=O)Nc1nc2c(OC)ccc(C(=O)CBr)c2s1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2c(OC)ccc(-c3csc(C)n3)c2s1
Reaction time: 4 h

Procedure:
1.3 g of (7-bromoacetyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (0.0036 Mol) and 0.27 g of thioacetamide (0.0036 Mol) were dissolved in dioxane (30 ml) and stirred for 4 hrs. at 70° C. After evaporation of half of the solvent water (40 ml) was added and the pH adjust to 7 with sat. NaHCO3. A solid precipitated, which was isolated and then subjected to column chromatography on silicagel using ethyl acetate as eluent. The title product was isolated as an off-white solid (27%); F.p.: 186-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:20]([C:22]1[C:27](F)=[CH:26][CH:25]=[CH:24][N:23]=1)#[N:21]>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:6][C:27]1[C:22]([C:20]#[N:21])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: N#Cc1ncccc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of 2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem. Pharm. Bull, 1985, 33, 565-71) in N,N-dimethylacetamide (29 mL). The reaction was heated at 80° C. for 4 h, quenched with water and extracted with diethyl ether (3×). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M+1).
Reaction SMILES: [OH:1][CH:2]1[C:27]2[C:19](=[CH:20][C:21]3[O:25][CH2:24][O:23][C:22]=3[CH:26]=2)[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3]1.[H-].[Na+].I[CH3:31].O>C1COCC1>[CH3:31][O:1][CH:2]1[C:27]2[C:19](=[CH:20][C:21]3[O:25][CH2:24][O:23][C:22]=3[CH:26]=2)[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]2=[O:18])[CH2:3]1
Reactant: CI
Reactant: CCCCCN1C(=O)C2(CC(O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCN1C(=O)C2(CC(OC)c3cc4c(cc32)OCO4)c2ccccc21
Yield: 57 %

Procedure:
To a solution of 7-hydroxy-1′-pentyl-6,7-dihydrospiro[indeno[5,6-d][1,3]dioxole-5,3′-indol]-2′(1′H)-one (0.05 g, 0.14 mmol) in THF (10.0 mL) was added sodium hydride (0.01 mg, 0.21 mmol) at 0° C. The reaction mixture was stirred for half an hour followed by the addition of iodomethane (0.50 mL). The mixture was stirred at ambient temperature for two hours, then poured into water (100 mL), and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.03 g, 57%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.26-7.18 (m, 1H), 6.98-6.82 (m, 4H), 6.10 (s, 1H), 5.88 (s, 2H), 5.26 t, 1H), 3.88-3.63 (m, 2H), 3.45 (s, 3H), 2.71-2.54 (m, 2H), 1.80-1.65 (m, 2H), 1.45-1.29 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 148.9, 148.4, 142.4, 136.8, 136.6, 135.1, 128.1, 123.1, 122.6, 108.5, 105.0, 103.2, 101.5, 82.7, 57.9, 55.6, 43.4, 40.3, 29.1, 27.2, 22.4, 14.0: MS (ES+) m/z 402.4 (M+23).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[CH3:15]S(C)=O>>[CH3:15][N:9]1[C:8]2[CH:14]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:12][CH2:11][C:10]1=[O:13]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: CS(C)=O
Product: CN1C(=O)COc2ccc([N+](=O)[O-])cc21

Procedure:
The title compound was prepared from 6-nitro-3-oxo-3,4-dihydro-(2H)-1,4-benzoxazine using the method described in Example 19. Yield: 3.01 g (56%) of product as a yellow solid. mp 185-187; 'H NMR (300 MHz, DMSO) and 7.968 (dd, J=8.9 Hz, 2H), 7.78 (d, J=2.5H 1H), 7.363 (d, J=8.9 2H), 4.799 (s, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, DMSO) and 164.430, 144.77, 135.913, 118.824, 115.808, 111.5142, 66.944, 20.82; Mass Spectrum M+ m/z 208.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>O1CCCC1.C(OCC)C.[Cl-].[Al+3].[Cl-].[Cl-]>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([Br:16])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(=O)C(Br)C1
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
A solution of (4-Oxo-cyclohexyl)-carbamic acid tert-butyl ester (10 grams, 46 mmol) and aluminum chloride (0.25 grams, 2 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0° C., then treated with bromine (2.4 mL, 46 mmol) over a period of 30 minutes. The reaction mass was stirred for 24 hours at 0-5° C. After completion of reaction, the obtained solids were filtered and lower filtrate was concentrated under vacuum. The obtained crude was triturated with diethyl ether and the resulted solids were filtered and dried under vacuum to obtain the title compound (9.0 grams).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FC(F)(F)CCCI
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1
Yield: 33.6 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 88 mg of sodium hydride (60% in oil), and 0.53 g of 1-iodo-4,4,4-trifluorobutane, and according to the process described in the Production Example 1, there was obtained 0.25 g of 2-(4,4,4-trifluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (78)).
Reaction SMILES: Cl.C(CCP(CCC(O)=O)CCC(O)=O)(O)=O.[CH3:18][N:19]([CH2:33][C:34]([CH3:39])([S:36]SC)[CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[N:26]=[C:25]([CH2:31][OH:32])[CH:24]=1>O.CO>[SH:36][C:34]([CH3:39])([CH3:35])[CH2:33][N:19]([CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][OH:32])[N:26]=[C:27]([CH2:29][OH:30])[CH:28]=1
Reactant: CSSC(C)(C)CN(C)CCOc1cc(CO)nc(CO)c1
Agent: Cl
Agent: O=C(O)CCP(CCC(=O)O)CCC(=O)O
Solvent: CO
Solvent: O
Product: CN(CCOc1cc(CO)nc(CO)c1)CC(C)(C)S
Reaction time: 2 h
Yield: 98 %

Procedure:
A solution of 198 mg of tris(2-carboxyethyl)phosphine hydrochloride in 730 μl of water is added to 80 mg of 4-{2-[methyl(2-methyl-2-(methyldisulphanyl)propyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine in solution in 1.95 ml of methanol. After 2 h at AT, the mixture is concentrated under RP and the residue is taken up in 10 ml of water. The aqueous phase is brought to pH=8 by addition of an aqueous sodium hydroxide solution and then extracted 2× with AcOEt. The combined organic phases are washed with a saturated aqueous NaCl solution and concentrated under RP. 68 mg of 4-{2-[(2-mercapto-2-methylpropyl)(methyl)amino]ethoxy}-2,6-bis(hydroxymethyl)pyridine are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:24])([F:23])[F:22])=[C:6]([C:8]2[S:9](=[O:20])(=[O:19])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[OH:18])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][CH2:37]Cl)[CH3:35]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([F:23])([F:24])[F:22])=[C:6]([C:8]2[S:9](=[O:19])(=[O:20])[CH2:10][C:11]3[N:12]=[CH:13][CH:14]=[N:15][C:16]=3[C:17]=2[O:18][CH2:37][O:36][CH2:34][CH3:35])[CH:7]=1
Reactant: O=S1(=O)Cc2nccnc2C(O)=C1c1cc(Cl)ccc1C(F)(F)F
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCOC1=C(c2cc(Cl)ccc2C(F)(F)F)S(=O)(=O)Cc2nccnc21
Temperature: 25 °C

Procedure:
To a mixture of 7-(5-chloro-2-trifluoromethyl-phenyl)-6,6-dioxo-5,6-dihydro-6-thia-1,4-diaza-naphthalen-8-ol (Compound C7 of Table C) (0.54 g) and N,N-diisopropylethylamine (0.25 ml) in N,N-dimethylformamide (5 ml) under nitrogen atmosphere was added chloromethyl ethyl ether (0.20 ml) and the reaction mixture was stirred at ambient temperature. After 2 hr further diisopropylethylamine (0.10 ml) and chloromethyl ethyl ether (0.10 ml) were added. After a further 3 hours stirring the reaction was concentrated and the residue purified by chromatography on silica gel (eluent: 0-100% v/v ethyl acetate in hexane) to give 7-(5-chloro-2-trifluoromethyl-phenyl)-8-ethoxymethoxy-5H-6-thia-1,4-diaza-naphthalene 6,6-dioxide (0.276 g) 1H-NMR (400 MHz, CDCl3): 1.04 (3H, t), 3.25-3.41 (2H, m), 4.76-4.87 (2H, q), 5.13 (1H, d), 5.33 (1H, d), 7.58-7.61 (2H, m), 7.76 (1H, d), 8.62 (1H, d), 8.73 (1H, d).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:9]([C:11](C#N)=[C:12]([C:15]#[N:16])[C:13]#[N:14])#[N:10]>O>[C:9]([C:11]1[C:12]([C:13]#[N:14])=[C:15]([NH2:16])[N:3]([C:4]([NH2:6])=[O:5])[N:2]=1)#[N:10]
Reactant: N#CC(C#N)=C(C#N)C#N
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1nn(C(N)=O)c(N)c1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a mixture of semicarbazide hydrochloride (11.2 g, 0.1 mol), water (200 ml) and sodium hydroxide (4.0 g, 0.1 mol) cooled in an ice-bath was added dropwise tetracyanoethylene (12.8 g, 0.1 mol). The reaction mixture was warmed to room temperature, stirred for 1.5 hours and then allowed to stand for 24 hours. The white precipitate which formed during the course of the reaction was collected by filtration and washed with water to afford 15.6 g (89%) of 3-cyano-4-cyano-5-amino-1H-pyrazole-1-carboxamide as a white solid, m.p. 225° C. (dec.) when dried at 85° C. in high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.[CH3:29][O:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+]>C(Cl)Cl>[F:18][CH:17]([F:19])[C@@H:14]1[C@@H:13]2[C@@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:37]([C:34]4[CH:33]=[N:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=4)=[O:38])[CH:3]=[CH:4][C:5]=3[F:28])([N:9]=[C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[S:11][CH2:12]2)[CH2:16][O:15]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)F)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: [PH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)F)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
To a stirred solution of tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (2.70 g) and 5-methoxypyrazine-2-carboxylic acid (1.25 g, described in WO2009/091016), in DCM (30 mL) was added N,N-diisopropylethylamine (3.5 mL) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (4.2 g). The reaction mixture was stirred at RT for 18 h, concentrated under vacuum to circa 20 mL, and sodium bicarbonate (sat., aq., 100 mL) was added. The mixture was extracted with EtOAc (2×150 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (0% to 25% EtOAc in DCM gradient) to afford the title compound (1.74 g) as a white solid. NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.76-2.88 (m, 1H), 2.95-3.28 (m, 1H), 3.34-3.53 (m, 1H), 3.83-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.68 (m, 2H), 5.98 (dt, J=3.6, 56.8 Hz, 1H), 7.07-7.20 (m, 1H), 7.36-7.48 (m, 1H), 7.96-8.04 (d, J=7.8 Hz, 1H), 8.20 (d, J=1.0 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.53 (br. s., 1H)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][NH:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3cc(CNC4CCNC4)ncn3)ccc21

Procedure:
(±)-3-({6-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 mg, 3.30 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is then extracted with EtOAc (3×) and the combined organic layers are washed with water, brine, dried with Na2SO4, filtered, and condensed. The residue is purified by FCC (0-10% 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 496.8 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.65 (s, 1 H), 8.36 (d, J=8.84 Hz, 1 H), 8.06 (s, 1 H), 7.95 (d, J=3.54 Hz, 1 H), 7.88 (s, 1 H), 7.57 (t, J=7.83 Hz, 1 H), 7.44 (d, J=7.83 Hz, 1 H), 7.42 (d, J=2.27 Hz, 1 H), 7.03-7.13 (m, 2 H), 6.75 (d, J=3.79 Hz, 1 H), 3.80-3.85 (m, 2 H), 2.81-3.02 (m, 3 H), 2.52-2.75 (m, 2 H), 2.19-2.35 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14][CH3:15].[OH:16]OS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[OH:1][C:2]1[C:9]([C:10]([F:12])([F:13])[F:11])=[CH:8][C:5]([C:6]([OH:16])=[O:7])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
A suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzaldehyde (1.03 g, 4.68 mmol) and Oxone™ (3.45 g, 5.61 mmol) in DMF (10 mL) was stirred at RT for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and the solution was washed sequentially with 1M HCl (40 mL) and brine (4×40 mL). The solvent was removed in vacuo and the residue was purified by silica gel chromatography (80 g, 0-10% MeOH in DCM) to afford 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 35%) as a white solid: m/z 235 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 13.01 (1H, br s), 10.74 (1H, br s), 7.68 (2H, dd), 3.92 (3H, s).