Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[N+:26]([O-])=O)[NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]3[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=3)=[O:44])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]3[CH:23]=[CH:24][C:25]4[NH:26][C:49]([C:48]5[CH:51]=[CH:52][C:45]([C:43](=[O:44])[NH:42][C:39]6[CH:40]=[CH:41][C:36]([N:33]7[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]7)=[CH:37][CH:38]=6)=[CH:46][CH:47]=5)=[N:1][C:4]=4[CH:5]=3)=[O:22])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CN1CCN(c2ccc(NC(=O)c3ccc(C=O)cc3)cc2)CC1
Reactant: CN1CCN(c2ccc(C(=O)Nc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)cc2)CC1
Product: CN1CCN(c2ccc(NC(=O)c3ccc(-c4nc5cc(NC(=O)c6ccc(N7CCN(C)CC7)cc6)ccc5[nH]4)cc3)cc2)CC1

Procedure:
Compound 196 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-(4-methylpiperazin-1-yl)benzoyl)aniline and 4-(4-(4-methylpiperazin-1-yl)phenyl)aminocarbonylbenzaldehyde. [M+H]+ calcd for C37H40N8O2: 629.33; found: 629.16.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.CS(O)(=O)=O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:24]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(C(C)=O)cc3CC12
Reaction time: 1 h

Procedure:
A mixture of (±) (1S,9aS/1R,9aR) N-[(9,9a-dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (X diastereomer B, EXAMPLE 11, 8 mg), methane sulfonic acid (0.5 ml), and acetic anhydride (10 μl) is stirred in methylene chloride (0.2 ml) from 0° to 20° for 19.5 hours. After this time the mixture is cooled in an ice bath and additional acetic anhydride (10 μl) is added. The mixture is stirred for one hour then added to a small amount of ice and saturated aqueous sodium bicarbonate (7 ml) is added, then solid sodium bicarbonate is added until alkaline. The mixture is then extracted with methylene chloride (5×, 20 ml total). The combined extract layers provide 8 mg of material. The 8 mg is then purified by chromatography (5 cm×0.5 cm disposable pipet, 40-63 μ silica) eluting with 1% and 2.5% methanol/methylene chloride gradient while collecting 0.4 ml fractions. The appropriate fractions are pooled and concentrated to provide the title compound.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:35]>CN(C=O)C.O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:16]=[CH:15][C:14]=3[N:13]([CH3:35])[C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(S(=O)(=O)c4ccccc4)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)CCN(C(=O)c1ccccc1)CC2
Reaction time: 0.5 h

Procedure:
A 0° mixture of 3-benzoyl-9-(phenylsulfonyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (Step II, 1.61 g, 3.74 mmol) in dry DMF (18 mL) is treated with sodium hydride (60% in oil, 165 mg, 4.11 mmol). After 30 min, the mixture is treated with iodomethane (256 μL, 4.11 mmol) and allowed to slowly warm to 20-25° under nitrogen over 16 hr. The resultant mixture is diluted with H2O and filtered. The residual solid is triturated with refluxing methanol, isolated, and dried in the vacuum oven at 50° to give the desired indole, imp=254-255°.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:18]CC)[CH2:6]C[Si](OCC)(OCC)OCC)[CH3:3].C(=O)CCC>O>[CH:2]([OH:4])=[CH2:3].[C:5]([O:4][CH:2]=[CH2:3])(=[O:18])[CH3:6]
Reactant: CCOC(CC[Si](OCC)(OCC)OCC)OCC
Agent: Cl
Solvent: O
Solvent: CCCC=O
Product: C=CO
Product: C=COC(C)=O
Temperature: -2 °C

Procedure:
2,683 ml of distilled water, 1,114 ml of a 20% by weight HCl and 1,190 ml of a 19.7% by weight aqueous solution of a fully hydrolyzed polyvinyl alcohol, viscosity 3.68 mPas (DIN 53015; Höppler method; 4% by weight aqueous solution), were charged to a 6 liter glass reactor and cooled to −2° C. within a period of one hour, with stirring. A mixture made from 2.5 g of 3,3-diethoxypropyltriethoxysilane and 188 ml (151.6 g) of butyraldehyde, cooled in advance to −4° C., was then added over a period of 5 minutes, with an attendant rise in internal reactor temperature to −0.7° C. The mixture was then rapidly cooled again to −2° C. 3 minutes after addition of the mixture the reaction mixture, which had until then been clear, was observed to become cloudy, and the product precipitated as little as 5 minutes later. After 40 minutes reaction time at −2° C. the temperature was increased to 25° C. over a period of 3.5 hours, and this temperature was maintained for a further 2 hours. The product was then separated by suction filtration and washed with distilled water until the filtrate gave a neutral reaction. The moist product was dried to a solids content of at least 98%, initially at 22° C. and then at 35° C. in vacuo, yielding a modified polyvinyl butyral having 17.8% by weight of vinyl alcohol units, 1.5% by weight of vinyl acetate units, and 80.7% by weight of vinyl butyral units. The viscosity (DIN 53015; Höppler method; 10% by weight ethanolic solution) was 25.1 mPas. The Si content was determined to be 0.05% by weight.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](Cl)=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:18]([C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=1)=[O:19])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CCCC[n+]1c(C)csc1C
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 3-(trifluoromethyl)benzoyl chloride (33.4 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.91-0.98 (m, 3 H) 1.34-1.47 (m, 2 H) 1.61-1.72 (m, 2 H) 2.30-2.33 (m, 3 H) 4.07-4.16 (m, 2 H) 6.56-6.60 (m, 1 H) 6.66-6.72 (m, 1 H) 7.69 (t, 1 H) 7.80 (d, 1 H) 8.17-8.23 (m, 1 H) 8.27 (d, 1H); MS (ESI) positive ion 342 (M+H).
Reaction SMILES: [C:1](/[CH:4]=[C:5]1/[CH:6]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]/1)([OH:3])=[O:2].S(Cl)(Cl)=O.Cl[CH2:38]Cl>>[CH3:38][O:2][C:1](/[CH:4]=[C:5]1/[CH:6]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]/1)=[O:3]
Reactant: ClCCl
Reactant: O=C(O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(E)-3-[2-(2-Carboxymethylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (36.8 mg) was suspended in dichloromethane and the mixture was cooled in an ice bath. To this was added thionyl chloride (0.1 ml). After the reaction mixture was stirred at room temperature for 4 hours, the solvent was evaporated in vacuo. The residue was dissolved in methanol (2 ml), and stirred at room temperature for 10 minutes. Methanol was evaporated in vacuo and the residue was partitioned between dichloromethane (10 ml) and saturated aqueous sodium bicarbonate. After an additional extraction with dichloromethane (10 ml), the combined extracts were washed with brine (10 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo. The oily residue was crystallized from ethyl acetate to give colorless crystals of (E)-3-[2-(2-methoxycarbonylmethylene cyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (36.3 mg). The spectroscopic data for this compound were identical to those for the authentic sample obtained in Example 31.
Reaction SMILES: C(OC[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)C(C)=C.[C:19](OCC(C)C)(=O)C(C)=C>>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH3:8])[CH3:19]
Reactant: C=C(C)C(=O)OCC(C)C
Reactant: C=C(C)C(=O)OCCCCCCCCCCCC
Product: CCCCCCCCCC(C)C

Procedure:
24 g of helio fast blue HG (C.I. no. 74160), 6 g of a copolymer formed from 75% of lauryl methacrylate and 25% of isobutyl methacrylate with a molecular weight of 150 000, and 210 g of isododecane are mixed for 10 hours using a bead vibrating mill. 100 g of the dispersion obtained are diluted with 100 g of isododecane and reacted with vigorous stirring over a period of 30 minutes at 25° C. with a mixture of 4.5 g of isobutyl cyanoacrylate and 1.5 g of allyl cyanoacrylate. The dispersion was stirred for a further 2 hours at 25° C., then centrifuged and the isolated solid matter was washed with isododecane, centrifuged again and dried. 30 g of coated blue pigment are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].CCCCCC>C(OCC)(=O)C>[C:2]1([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: NC(=O)c1ccccc1N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=O)c1ccccc1Nc1ccccc1
Yield: 69.7 %

Procedure:
Following the general procedure, bromobenzene (55 μL, 0.5 mmol) was coupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reaction time of 15 h. Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 74 mg (70%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH3:20][Mg]Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:20])[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1
Reactant: Cc1ccc(F)cc1C#Cc1cnc(Cl)cc1C=O
Reactant: C[Mg]Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)isonicotinaldehyde (705 mg, 2.6 mmol) in tetrahydrofuran (11 mL) cooled at −15° C. was added a solution of 3.0M methylmagnesium chloride in tetrahydrofuran (1 mL, 3.1 mmol) dropwise over 1 minute. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with a few drops of saturated aqueous ammonium chloride solution, tetrahydrofuran was evaporated in vacuo, and the resulting residue was redissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a colorless oil that was redissolved in dichloromethane (10 mL) and treated with Dess-Martin periodinane (1.4 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (700 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[C:21]1([CH2:27]C#N)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:27]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2)cc1
Reactant: N#CCc1ccccc1
Product: c1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4)cc23)cc1

Procedure:
The title compound, light grey solid (37 mg, 29%), MS (ISP) m/z=338.3 [(M+H)+], mp 163° C., was prepared in accordance with the general method of example 1 from 5-(4-nitro-phenyl)-1-phenyl-1H-pyrazole (intermediate A) (100 mg, 353 μmol) and commercially available 2-phenyl-acetonitrile.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17](O)=[O:18].CN(C)CCCN=C=NCC.Cl.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl.CN(C=O)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:17]([NH:42][C:41]1[CH:43]=[CH:44][C:38]([F:37])=[CH:39][CH:40]=1)=[O:18]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)cc1)c1cc2cc([N+](=O)[O-])ccc2n1Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
389 mg (1.17 mmol) of 1-(2,4-difluorobenzyl)-5-nitro-1H-indole-2-carboxylic acid from Example XXII, 336 mg (1.76 mmol) of N′-(3-dimethylaminopropyl)-N-ethyl-carbodiimide×HCl and 71.5 mg (0.59 mmol) of 4-dimethylaminopyridine are initially charged in 30 ml of a 10:1 dichloromethane:DMF mixture. 156 mg (0.13 ml, 1.40 mmol) of 4-fluoroaniline are added, and the mixture is stirred at RT for 4 hours. For work-up the mixture is diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is washed with sat. sodium chloride solution, dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.Br[C:16]1[CH:17]=[C:18]([C:21]#[N:22])[O:19][CH:20]=1>>[CH3:11][CH:9]1[O:8][C:7]([CH3:13])([CH3:12])[C:6]2[CH:14]=[C:2]([C:16]3[CH:17]=[C:18]([C:21]#[N:22])[O:19][CH:20]=3)[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: N#Cc1cc(Br)co1
Reactant: CC1Nc2ccc(Br)cc2C(C)(C)O1
Product: CC1Nc2ccc(-c3coc(C#N)c3)cc2C(C)(C)O1

Procedure:
Prepared using the coupling procedure for Example 13 from 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine and 4-bromo-2-cyanofuran. A light brown solid: mp 116-118° C.; 1H-NMR (DMSO-d6) δ 8.43 (s, 1H), 8.06 (s, 1H), 7.38 (d, 1H, J=1.98 Hz), 7.25 (dd, 1H, J=7.93, 1.98 Hz) 6.58 (d, 1H, J=7.93 Hz), 6.37 (s, 1H), 4.77 (q, 1H, J=5.55 Hz), 1.50 (s, 3H), 1.46 (s, 3H), 1.27 (d, 3H, J=5.55 Hz); MS (ES) m/z 269 ([M+H]+); Anal. Calc. For C16H16N2O2: C, 71.62; H, 6.01, N, 10.44. Found: C, 71.55; H, 6.26, N, 10.17.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.[CH3:37][O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>ClCCl>[CH3:37][O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=4[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=3)=[O:12])[CH2:14][CH2:15]2)(=[O:50])=[O:51])=[CH:45][CH:44]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (80 mg, 0.2 mmol, 1.0 equiv; Example 122) in anhydrous dichloromethane (2 mL) was added N-ethyldiisopropylamine (51.3 mg, 69 μL, 0.4 mmol, 2.0 equiv; [CAS RN 7087-68-5]) and methyl 3-(4-chlorosulphonyl)phenylproprionate (57.8 mg, 0.22 mmol, 1.1 equiv; [CAS RN 374537-95-8]) and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 44 mg (35%) of the title compound as a light off-white powder. MS (ISP): 626.2 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH:5](C)[CH3:6])[CH:3]=O.[CH2:8]=[O:9].[CH3:10][OH:11].[OH-].[Na+]>C(O)=O>[CH:2]([C:5]([CH3:6])([CH2:10][OH:11])[CH2:8][OH:9])([CH3:3])[CH3:1]
Reactant: CO
Reactant: C=O
Reactant: CC(C)C(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CC(C)C(C)(CO)CO
Temperature: 50 °C
Yield: 92 %

Procedure:
A 4 l stirring flask with condenser and nitrogen blanketing was charged with crude 2,3-dimethylbutanal product (250 g, 2.5 mol) (88% 2,3-dimethylbutanal and 11% 4-methylpentanal) and formaldehyde (30% in water, 750 g, 7.5 mol) with 120 g of methanol. Over the course of 1.5 h, sodium hydroxide (25% in water, 645 g, 4 mol) was added dropwise and the batch was heated at 50° C. Following the addition of the base, the batch was stirred at 50° C. for a further 30 min and then adjusted to a pH of 7 with formic acid at room temperature. The phases were separated. The aqueous phase contained diol (˜12%) and so was extracted with amyl alcohol. The combined organic phases were freed under reduced pressure from methanol and amyl alcohol. The crude distillation of the product took place via a distillation bridge (109-135° C. at 4 mbar). The final distillation was carried out in a packed column (108-106° C. at 4 mbar). The product was obtained in a yield of 92% as a solid with a purity of 98%.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24]OS(C)(=O)=O)[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31].[Cl:35]CCl>O1CCCC1>[ClH:35].[CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]3[N:23]=[C:22]([CH2:24][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[S:21][N:20]=3)=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCCl
Reactant: COc1cccc2c(-c3nsc(COS(C)(=O)=O)n3)cn(CC3CCCCC3)c12
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)Cc1nc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)ns1
Product: Cl

Procedure:
To a solution of methanesulfonic acid 3-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-[1,2,4]thiadiazol-5-ylmethyl ester (93 mg, 0.2 mmol) in tetrahydrofuran (1 ml) was added diethylamine (0.22 ml, 2.13 mmol) and the reaction subjected to microwave irradiation at 150° C. for 15 minutes. The reaction was poured into a separating funnel and diluted with dichloromethane (40 ml). The combined organics were washed with 5% aqueous sodium carbonate solution (2×20 ml), brine (2×20 ml), dried over magnesium sulfate and the solvent removed in vacuo. The resulting residue was purified by flash column chromatography to afford the title compound (54 mg, 0.13 mmol) as the free base. The free base was dissolved in dichloromethane and hydrogen chloride (2M solution in diethyl ether; 1.0 ml, 2.0 mmol) was added. The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt. 1H NMR (400 MHz, CD3OD): 0.95-1.12 (2H, m), 1.16-1.27 (3H, m), 1.45 (6H, t, J 7), 1.55-1.63 (2H, m), 1.63-1.8 (3H, m), 1.8-1.95 (1H, m), 3.28-3.32 (4H, m), 3.97 (3H, s), 4.3 (2H, d, J 7), 4.96 (2H, s), 6.79 (1H, d, J 8), 7.13 (1H, t, J 8), 7.95 (1H, s), 8.04 (1H, d, J 8); EsIMS: m/z 413.1 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH2:8][N:9]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]2[N:15]=[C:14]3[N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:17]=[C:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[CH:24]=O)[CH2:7][CH2:6]1.[F:30][C:31]([F:45])([F:44])[C:32]1[CH:33]=[C:34]([CH2:42][NH2:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.C([BH3-])#N.[Na+]>CO>[F:30][C:31]([F:44])([F:45])[C:32]1[CH:33]=[C:34]([CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=1)[CH2:42][NH:43][CH2:24][C:11]1[CH:12]=[C:13]2[C:18]([CH3:19])=[N:17][N:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:14]2=[N:15][C:10]=1[N:9]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[CH2:8][CH:5]1[CH2:7][CH2:6]1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(C=O)cc12
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Reaction time: 0.33 h

Procedure:
Acetic acid (2.82 g, 46 mmol) was added to a mixture of 6-(bis(cyclopropylmethyl)amino)-1-(tert-butyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (8 g, 23 mmol) and (3,5-bis(trifluoromethyl)phenyl)methanamine (5.7 g, 23 mmol) in methanol at 0° C. The resulting mixture was stirred continuously for 20 min. Sodium cyanoborohydride (4.5 g, 70 mmol) was added portion wise to the reaction mixture at 0° C. and the mixture was stirred for 1 h. After which the mixture was quenched with water, organic layer was separated, washed with brine, dried and evaporated to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=O.[NH3:17]>>[NH2:17][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: N
Product: NC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
4-(Methoxycarbonyl)-3-nitrobenzoic acid (100 g, 0.44 mol) was taken into concentrated aqueous ammonia (37w %, 500 mL), and the resulting yellow solution was allowed to stir at room temperature over 12 hours. The solution was then reduced in volume to approximately 300 mL by rotary evaporation, and the solution was acidified to pH 2 by portion-wise addition of concentrated aqueous hydrochloric acid. The thick precipitate was collected by filtration and dried in vacuo to afford 4-(aminocarbonyl)-3-nitrobenzoic acid (51 g, 60% yield). 1H-NMR (d6-DMSO): 8.42 (d, 1H), 8.27 (dd, 1H), 8.26 (br s, 1H), 7.86 (br s, 1H), 7.76 (d, 1H).