Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:17]([C@H:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:24](C)[C:25](=O)OC(C)(C)C)[S:14]2)[CH2:10]1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH3:25][NH:24][C:13]1[S:14][C@H:15]2[O:16][C@H:17]([C@H:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[C@@H:9]([OH:8])[CH2:10][C@H:11]2[N:12]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H]([C@H](O)C(F)(F)F)O[C@@H]2S1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CNC1=N[C@@H]2C[C@H](O)[C@@H]([C@H](O)C(F)(F)F)O[C@@H]2S1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.060 g, 0.13 mmol) and PMB (0.10 g, 0.67 mmol) in anhydrous DCM (4 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 0.60 mL, 0.60 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath warmed to 0° C. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:12), affording (3aR,5S,6S,7aR)-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.030 g, 82%). 1H NMR (400 MHz, CD3OD) δ 6.15 (d, J=6.5 Hz, 1H), 4.38-4.34 (m, 1H), 4.11-4.07 (m, 1H), 4.05-3.98 (m, 1H), 3.68 (dd, J=5.6, 7.1 Hz), 2.84 (s, 3H), 2.20-2.09 (m, 2H); 13C NMR (100 MHz, CD3OD) δ 163.99, 126.24 (q, J=280.7 Hz), 91.08, 75.0 (br.), 72.12 (q, J=29.7 Hz), 70.17, 67.00, 33.65, 30.80; MS, (ES, m/z) [M+H]+ 287.1.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[S:20][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[S:20][C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2sc3ccncc3c2Nc2ccc(Br)cc2F)O1
Solvent: CO
Product: O=C(NOC[C@H](O)CO)c1sc2ccncc2c1Nc1ccc(Br)cc1F

Procedure:
A solution of 3-(4-bromo-2-fluoro-phenylamino)-thieno[3,2-c]pyridine-2-carboxylic acid ((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-amide (18 mg, 0.036 mmol) in methanol (1 ml) was loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was then washed with methanol (15 ml) before the desired product was eluted using 2M ammonia in MeOH and the eluent collected then concentrated to give a residue. The residue was purified by flash chromatography (Si-SPE, DCM:MeOH, gradient 100:0 to 94:6) to afford the title compound as an off white solid (9 mg, 53%): LCMS (method A): RT=5.59 min, M+H+=456/458. 1H NMR (d4-MeOH, 400 MHz) 8.60 (s, 1H), 8.40 (d, J=5.7 Hz, 1H), 7.94 (d, J=5.7 Hz, 1H), 7.39 (dd, J=10.6 Hz, 2.2 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.80 (dd, J=8.5 Hz, 8.5 Hz, 1H), 4.01-4.10 (m, 1H), 3.89-4.00 (m, 2H), 3.57-3.67 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10]Br>C(O)(=O)C>[Br:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:2]([CH3:1])[C:3]=1[NH2:4]
Reactant: Cc1ccc(N)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C)c(N)c(Br)c1
Reaction time: 0.33 h

Procedure:
To a solution of 50.0 g (0.413 mol) of 2,4-dimethylaniline in 1500 cm3 of glacial acetic acid, 21.2 ml (65.6 g, 0.410 mol) of bromine was added dropwise with vigorous stirring over ca. 20 minutes. This mixture was stirred for 2 hours at 40° C. The precipitate that formed was filtered off, washed with 50 ml of acetic acid, and dried in air. The resulting white solid was added to a solution of 100 g of potassium hydroxide in 400 ml of water. This mixture was stirred for 30 minutes. The crude product was extracted with 3×100 ml of dichloromethane. The combined extracts were dried over Na2SO4 and evaporated to dryness. Fractional distillation gave yellowish liquid, bp 83-85° C./1 mm Hg. Yield 46.9 g (57%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: CCCCC(CC)CBr
Solvent: CO
Product: CCCCC(CC)COc1ccc(OC)cc1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
Sodium metal (6.50 g, 283 mmol) was dissolved in dry methanol (100 ml) under Ar to give a 2.5M solution of sodium methoxide. A solution of 4-methoxyphenol (29.3 g, 236 mmol) in dry methanol (150 ml) was added and this mixture was heated to reflux for 30 min. After cooling to room temperature, a solution of 1-bromo-2-ethylhexane (46.5 g, 259 mmol) in dry methanol (150 ml) was added dropwise. The mixture was then heated to reflux for 18 hours. The solvent was removed in vacuo, the residue dissolved in ether (200 ml), washed with dilute aqueous sodium hydroxide (500 ml) and water (500 ml), dried over MgSO4 and concentrated in vacuo again. Distillation at 120° C./0.1 mm Hg afforded 24.2 g (43%) 1-methoxy-4-(2'-ethylhexyloxy)benzene.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]1.C(N(CC)CC)C.[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>CO.O>[N+:21]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([NH:1][CH2:2][C:3]2([CH2:12][OH:13])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH2:5][NH:4]2)=[O:29])=[CH:31][CH:32]=1)([O-:23])=[O:22]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: NCC1(CO)NCC(O)C(O)C1O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccc([N+](=O)[O-])cc1
Reaction time: 24 h
Yield: 27.1 %

Procedure:
5.4 g of 2-aminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine are dissolved in 50 ml of a methanol/water mixture (1:1), and 3.92 ml of triethylamine and, at -5° C., 5.44 g of 4-nitrobenzoyl chloride are added. The mixture is stirred for 24 hours and evaporated in vacuo, the residue is taken up in ether/water and the phases are separated. The aqueous phase is extracted once with ether and the product phase is then evaporated. The residue is dissolved in a little water and the solution is discharged onto a column 120 cm long and 4 cm wide which contains cellulose as the stationary phase and 99% pure acetone as the mobile phase. The column is eluted successively with 99% pure acetone, 95% pure acetone and finally 90% pure acetone. The individual fractions are examined by thin layer chromatography to determine their content of the required compound. The fractions containing the desired product are collected and evaporated. 2.6 g of 2-(4-nitrobenzoylaminomethyl)-2-hydroxymethyl-3,4,5 -trihydroxypiperidine are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](OC(C)(C)C)=[O:15])[CH2:9]1.O1CCOCC1.N1C=CC=CC=1.[Cl:39]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([Cl:39])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
(R)-tert-butyl 3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carboxylate (219 mg, 0.603 mmol) was dissolved in 4M HCl in 1,4-dioxane (20 mL, 80 mmol) and stirred for 30 min. LC-MS showed removal of the Boc protecting group. The reaction mixture was concentrated and redissolved dry CH2Cl2 (5 mL). Pyridine (122 μL, 1.51 mmol, 2.5 equiv) was added. This solution was added dropwise under N2 to a solution of triphosgene (188 mg, 0.63 mmol, 1.05 equiv) in dry CH2Cl2 (5 mL) at −78° C. After 10 min, the reaction mixture was warmed to rt and stirred for 2 h. LC-MS showed the reaction was complete. 5% aq HCl (15 mL) was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×30 ml). The combined organic layers were washed with satd aq NaHCO3 and brine, and dried over Na2SO4. Concentration afforded (R)-3-((R)-(3-methoxypropoxy)(phenyl)-methyl)piperidine-1-carbonyl chloride (188 mg, 96%) as a yellow oil. LC-MS (3 min) tR=1.83 min, m/z 344 (M+H2O). The crude product was used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15][N:28]=[N+:29]=[N-:30])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02 mol) were warmed to ˜50° C. in DMSO (30 mL). After 2 hours the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated to give an oil 1.54 g, 79%. Further purification by flash chromatography (95% hexane/EtOAc) gave an oil. [α]D=−8.3 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:19])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])C.[BrH:20]>CS(C)=O>[NH2:19][C:14]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH:8]=[N:7][C:6]([C:4]([OH:3])=[O:5])=[N:18][C:17]=3[C:16]=2[C:15]=1[Br:20]
Reactant: Br
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2n1
Solvent: CS(C)=O
Product: Nc1ccc2[nH]c3cnc(C(=O)O)nc3c2c1Br
Reaction time: 2 h

Procedure:
One gram of 8-amino-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 11) is combined with such an amount of dimethyl sulfoxide that a clear solution is produced. Then, at 0°-5° C., the same amount of 48% aqueous hydrobromic acid is added dropwise and the mixture stirred thereafter for another 2 hours at this temperature, thus obtaining the ethyl ester of 8-amino-9-bromo-5H-pyrimido[5,4-b]indole-2-carboxylic acid.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:17])[NH:8]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:17])[NH:8][CH:7]2[CH3:6])=[O:4]
Reactant: CC1NC(=O)Nc2ccccc21
Reactant: O=C(Cl)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1NC(=O)Nc2ccc(C(=O)CBr)cc21

Procedure:
2-Bromoacetyl chloride (9.7 g) is added dropwise to a stirred mixture of 3,4-dihydro-4-methyl-2(1H)-quinazolinone (5 g), anhydrous aluminum chloride (10.3 g) and carbon disulfide (100 ml) under nitrogen. The reaction mixture is refluxed for about 18 hours, the carbon disulfide decanted, and the residue treated with hydrochloric acid (6N) and ethyl acetate. The layers are separated, and the aqueous layer extracted with ethyl acetate and the combined ethyl acetate extracts washed with sat'd. aqueous sodium bicarbonate and water and dried. The dried organic extract is filtered and the filtrate evaporated, affording the desired product as a solid, which is used without further purification, M.P. 188°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1.C(Br)CCCCCCC.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1
Reactant: Brc1cc2c3c(ccc4cc(Br)cc(c43)C2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCBr
Solvent: O
Product: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Yield: 133.6 %

Procedure:
2,6-dibromo-4H-cyclopenta[def]phenanthrene (2.6 g, 7.7 mmol) and octyl bromide (3.6 g, 18.5 mmol) in a 50 ml round bottom flask were dissolved with toluene (10 ml), and TBAB (tetrabutylammoniumbromide) (0.125 g, 0.385 mmol) was added thereto. A solution of NaOH (3.1 g, 77 mmol) in water (50 ml) was added to the reaction mixture, and the resultant solution was refluxed for two days. After the reaction was terminated, the reaction solution was extracted with chloroform. The organic layer was dried over MgSO4, concentrated, and purified by silica gel column chromatography (eluent: n-hexane). The eluate was distilled under a reduced pressure to remove unreacted octyl bromide, thereby giving a compound 2 (3.6 g, 80%).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[N:4]=1>Cl>[CH3:9][C:8]1[C:3]([OH:2])=[N:4][C:5]([CH3:13])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: COc1nc(C)c([N+](=O)[O-])cc1C
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c(C)nc1O
Temperature: 110 °C
Yield: 91.5 %

Procedure:
A solution of 2-methoxy-3,6-dimethyl-5-nitropyridine (32.3 g, 182 mmol) in 12 N hydrochloric acid (300 mL) was heated at 100° C. for 1 h. Analysis by TLC indicated that some starting material remained, so the reaction was heated at 110° C. for an additional 45 min. The reaction mixture was cooled to room temperature and poured onto ice (400 g). When the ice had melted and the temperature of the resulting thick brown suspension was still less than 0° C., the mixture was filtered. The solid cake was washed with water (100 mL) and allowed to dry on the filter for 30 min. The solid was then resuspended in cold (−10° C.) ethanol (150 mL), filtered, washed with cold ethanol (50 mL), and air-dried on the filter for 1 h to afford 3,6-dimethyl-5-nitropyridin-2-ol (28.0 g, 94% yield) as a tall powder: mp 263° C.; 1H NMR (400 MHz, DMSO-d) δ 12.42 (s br, 1H), 8.03 (s, 1H), 2.61 (s, 3H), 2.01 (s, 3H); LRMS (ESI) m/e 169.3 [(M+H)+, calcd for C7H9N2O3 169.1]. Anal. calcd. for C7H8N2O3: C, 50.00, H, 4.79, N, 16.66. Found: C, 50.01, H, 4.59, N, 16.75.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1.[C:21](O)(=[O:25])[CH:22]([CH3:24])[CH3:23].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.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[N:13][N:14]([CH:15]4[CH2:20][CH2:19][N:18]([C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]4)[C:5]=3[C:4]=2[N:3]=1
Reactant: Clc1ccc2ncc3nnn(C4CCNCC4)c3c2n1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(n2nnc3cnc4ccc(Cl)nc4c32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of 8-chloro-1-(piperidin-4-yl)-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridine (200 mg, 0.69 mmol), isobutyric acid (67 mg, 0.76 mmol), HATU (315 mg, 0.83 mmol) and DIEA (133 mg, 1.04 mmol) in DMF (5 mL) was stirred at r.t. overnight. Then water (10 mL) was added; the precipitate was collected and dried in vacuo to afford 1-(4-(8-chloro-1H-[1,2,3]triazolo[4,5-c][1,5]naphthyridin-1-yl)piperidin-1-yl)-2-methylpropan-1-one as a solid (200 mg).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6](OC)[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])C.[CH3:17][NH:18][NH2:19]>>[F:12][C:7]([F:13])([C:6]1[N:18]([CH3:17])[N:19]=[C:4]([OH:3])[CH:5]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: CNN
Reactant: CCOC(=O)C=C(OC)C(F)(F)C(F)(F)F
Product: Cn1nc(O)cc1C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 72 h
Yield: 29.8 %

Procedure:
62.03 g (0.25 mol) of 3-methoxy-3-pentafluoroethyl-2-propenoic acid ethyl ester was placed in a flask in ice water. 12.67 g (0.275 mol) of methylhydrazine was added with stirring keeping the temperature below 40° C. After the addition, the flask was removed from the ice bath and left standing for 3 days at ambient temperature. The reaction mixture was treated with 250 ml of aqueous sodium bicarbonate, washed with water, filtered and dried in vacuo to give 16.1 g (30% yield) of a white solid, m.p. 119°-124° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[C:15]([F:17])[CH:16]=1)[NH2:13].C(=O)([O-])[O-].[K+].[K+]>CCCCO>[F:9][C:10]1[CH:11]=[C:12]([N:13]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Fc1cc(F)cc(N2CCNCC2)c1

Procedure:
Bis(2-chloroethyl)amine hydrochloride (2.07 g, 11.60 mmol) was added to a solution of 3,5-difluoroaniline (1.50 g, 11.62 mmol) in n-BuOH (20 mL). After the resulting solution was refluxed for 48 h, anhydrous potassium carbonate (1.61 g, 11.62 mmol) was added. After being refluxed for another 24 h, the reaction mixture was cooled, partitioned between water and CHCl3, and the aqueous layer was extracted with CHCl3. The combined organic layer was washed with water, dried over Na2SO4, and evaporated to dryness. Et2O and 1 N HCl/EtOH were added to the residue, and the precipitate was filtered to give TC-IV-174 (1.17 g, 30%) as a white solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C(N(C(C)C)C(C)C)C.[O:29]=[C:30]1[NH:35][C:34]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:33]=2[O:32][CH2:31]1>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][S:40]([C:37]3[CH:38]=[CH:39][C:33]4[O:32][CH2:31][C:30](=[O:29])[NH:35][C:34]=4[CH:36]=3)(=[O:42])=[O:41])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: O=C1COc2ccc(S(=O)(=O)Cl)cc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1COc2ccc(S(=O)(=O)Nc3cc(-c4cc5ccccc5s4)c4[nH]ncc4c3)cc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a mixture of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 32 mg, 0.12) and ethyl-diisopropylamine (0.032 mL, 0.18 mmol) in DMF (1 mL) at room temperature and under an inert atmosphere was added 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonyl chloride (33 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 hours then concentrated under reduced pressure. The crude material was purified by preparative HPLC (20% to 80% acetonitrile/0.05 M aqueous ammonium acetate, buffered to pH 4.5 over 30 min at 20 mL/min; Hyperprep C18, 300 Å, 8 μm, 250×21.1 mm column) to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-sulfonic acid (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amide as a white solid (34 mg, 58%). LC/MS (Table 1, Method e) Rt 1.75 min; ESI−MS [M+H]+=475.3.
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([N:19]2[CH2:40][CH2:39][C:22]3([NH:26]/[C:25](=[N:27]/[C:28]([C:30]4[C:35]([NH2:36])=[N:34][C:33]([NH2:37])=[C:32]([Cl:38])[N:31]=4)=[O:29])/[NH:24][CH2:23]3)[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)(C)(C)C.[ClH:42]>O1CCOCC1>[NH2:36][C:35]1[C:30]([C:28](/[N:27]=[C:25]2/[NH:26][C:22]3([CH2:39][CH2:40][N:19]([C:17](=[O:18])[CH2:16][CH2:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:41])=[O:5])=[CH:14][CH:13]=4)[CH2:20][CH2:21]3)[CH2:23][NH:24]/2)=[O:29])=[N:31][C:32]([Cl:38])=[C:33]([NH2:37])[N:34]=1.[ClH:42]
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)N2CCC3(CC2)CN/C(=N\C(=O)c2nc(Cl)c(N)nc2N)N3)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(N)c(C(=O)/N=C2\NCC3(CCN(C(=O)CCc4ccc(OCC(=O)O)cc4)CC3)N2)nc1Cl
Reaction time: 1 h

Procedure:
[4-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]dec-8-yl}-3-oxo-propyl)-phenoxy]-acetic acid tert-butyl ester (WO09074575, Ex. 71, page 134) (28.4 g, 48.4 mmol) was slurried in 1,4-dioxane (260 ml) and stirred for 1 h. 4N HCl in dioxane (121 ml, 484 mmol) was added dropwise over 15 min and the reaction mixture was stirred overnight. The resulting yellow solid was filtered and washed with diethyl ether. The solid was slurried in fresh diethyl ether (500 ml) and sonicated for 30 min. The resulting solid was collected by filtration and dried in vacuo to afford the title product as a mono hydrochloride, di-dioxan solvate; LC-MS Rt 0.79 rains; 531.3 and 533.3 [M+H]+, Method 2minLC_v003.
Reaction SMILES: [F:1][C:2]1[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][OH:10])[N:6]=1.[C:30](Cl)(=[O:32])[CH3:31].O>N1C=CC=CC=1>[C:30]([O:10][CH2:9][CH2:8][CH2:7][C:5]1[N:6]=[C:2]([F:1])[N:3]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:4]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 1.67 h

Procedure:
A solution of 2-fluoro-4-(3-hydroxy)propyl-1-triphenylmethylimidazole (386 mg. in dry pyridine (2 ml.) and acetyl chloride (78.5 μl.) was heated with stirring at 85° for 100 minutes. The solution was poured into water (25 ml.) and the mixture extracted with CH2Cl2 (3×15 ml.). The extract was washed with water and brine, dried (MgSO4), filtered, evaporated, and the residue azeotroped with toluene. The resulting orange oil was purified by column chromatography on silica gel eluting with CH2Cl2 /MeOH 100:0 to 98:2 v/v to give 4-(3-acetoxy)propyl-2-fluoro-1-triphenylmethylimidazole (127 mg.) having the following n.m.r. in CDCl3 : 1.9 (m, 2H); 2.02 (s, 3H); 2.47 (t, 2H); 4.07 (t, 2H) 6.22 (s, 1H); 7.0-7.5 (m, 15H).
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH2:10][C:11]#[N:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC=CC=1C.[CH:21](O)=[O:22]>O>[C:11]([CH2:10][N:9]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH:21]=[O:22])#[N:12]
Reactant: O=CO
Reactant: CC(NCC#N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(c1ccccc1)N(C=O)CC#N
Temperature: 60 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
To a stirred mixture of 104.1 parts of (+)-2-[N-(1-phenylethyl)amino]acetonitrile and 1440 parts of dimethylbenzene are added dropwise 66 parts of formic acid (slightly exothermic reaction). Upon completion, stirring is continued for 3 hours at reflux temperature (water-separator). The reaction mixture is cooled to about 60° C. and washed successively with water, a sodium bicarbonate solution, a diluted sodium hydroxide solution and again twice with water. The organic phase is separated, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding (+)-N-(cyanomethyl)-N-(1-phenylethyl)-formamide (41%); m.p. 78.9° C.; [α] = +60.90° (1% CH3OH).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH2:13]([O:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([N+:30]([O-])=O)[CH:18]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:19]([NH:30][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:18]=1)[CH3:14]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CCOC(=O)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Product: CCOC(=O)c1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (2.06 g, 1.16 mmol) was reacted with the Product from Example 53b (3.18 g, 1.16 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (3.61 g, 59%).