Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[NH:15][C:14]=2[CH:23]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27].O>CN(C)C=O>[C:26]([N:15]1[C:14]2[CH:23]=[C:10]([CH2:9][O:1][Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3])[CH:11]=[CH:12][C:13]=2[S:18][C:17]2[N:19]=[CH:20][CH:21]=[N:22][C:16]1=2)(=[O:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)Nc1nccnc1S2
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1c2cc(CO[Si](C)(C)C(C)(C)C)ccc2Sc2nccnc21
Reaction time: 0.17 h

Procedure:
To a solution of 4.0 g of 8-(tert-butyldimethylsiloxymethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine in 50 ml of N,N-dimethylformamide was added 0.73 g of sodium hydride (60%) and the resulting mixture was stirred for 10 minutes. After adding 1.4 ml of acetyl chloride thereto, the resulting mixture was reacted at room temperature for 10 minutes. After adding water followed by extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting with ethyl acetate/hexane) to thereby give 2.5 g of the title compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].F[C:10]1[CH:15]=[CH:14][C:13]([S+:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1.[OH-].[Na+].[CH3:31][SH:32]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:31][S:32][C:26]1[CH:25]=[CH:24][C:23]([S+:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:27]=1
Reactant: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: CS
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Br-]
Solvent: ClCCl
Product: CSc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
26.7 g of 4-fluorophenyl diphenylsulfonium trifluoromethanesulfonate was dissolved in 200 g of dichloromethane in a reaction flask, in which the atmosphere was replaced with nitrogen. 200 g of 10 wt % sodium hydroxide aqueous solution, 5.8 g of tetra-n-butylammonium bromide, and 6.71 g of methanethiol were added. The mixture was stirred for 30 minutes at room temperature and transferred to a separatory funnel, shaken, and allowed to stand still. The water layer was removed. After the addition of 300 ml of distilled water, the mixture was shaken again and allowed to stand still. The water layer was removed. The resulting dichloromethane solution was dried using anhydrous magnesium sulfate and filtered. After evaporating dichloromethane from the dried solution, the residual liquid was dried under reduced pressure to obtain 19.2 g of 4-methylthiophenyl diphenylsulfonium trifluoromethane sulfonate.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([O-])(=O)C.[K+].C(#N)C.O.O1CCCCC1[O:44][CH2:45][CH2:46][N:47]1[CH:51]=[C:50](B2OC(C)(C)C(C)(C)O2)[CH:49]=[N:48]1.Cl>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:50]5[CH:49]=[N:48][N:47]([CH2:46][CH2:45][OH:44])[CH:51]=5)[CH:28]=[CH:27][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: OCCn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4-c4ccc(F)cc4F)nc2-3)cn1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.300 g, 0.000650 mol) and potassium acetate (0.1915 g, 0.001951 mol) in acetonitrile (1 mL, 0.02 mol) and water (2 mL, 0.1 mol). The reaction was thoroughly degassed and purged with N2 for 5 minutes. A solution of 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.2724 g, 0.0008455 mol) in acetonitrile (1 mL, 0.02 mol) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.07515 g, 6.504E-5 mol;) and the vial was sealed immediately. The reaction was heated to 140° C. for 20 minutes in the microwave. The mixture was diluted with methylene chloride and filtered through celite. Saturated NH4Cl was added and the mixture was extracted 3 times with methylene chloride. The organic layers were combined, dried with MgSO4 and concentrated. The crude was dissolved in methylene chloride (7 mL, 0.1 mol) and hydrogen chloride (4N in dioxoane, 0.38 mL, 0.001517 mol) was added dropwise. The reaction was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[NH:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]#[N:13].C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:11][C:12]#[N:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: N#CC[C@@H]1CCCN1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC[C@H]1CC#N
Temperature: 0 °C
Yield: 60.2 %

Procedure:
Acetyl chloride (8.6 g) was added dropwise to a stirred, cooled solution of ((S)-pyrrolidin-2-yl)acetonitrile hydrochloride (Intermediate 138, 8.0 g) and triethylamine (16.5 g) in DCM (80 mL) while maintaining the temperature at 0° C. The resultant solution was stirred at 0° C. for 30 minutes. Water was added and the layers were separated. The aqueous layer was further extracted with DCM and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by HPLC (C18) to give ((S)-1-acetylpyrrolidin-2-yl)acetonitrile (5.0 g) as a light yellow oil which was used directly without further characterisation.
Reaction SMILES: [S:1]([C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].C[Si]([C:24]#[N:25])(C)C>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][CH:9]([C:8]2[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:19][CH:18]=2)[C:24]#[N:25])=[CH:12][CH:13]=1
Reactant: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: Cc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-sulfamoylbenzylidene)-4-methylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 60%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:42])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[C:38]([CH3:40])[N:37]=[C:36]([CH3:41])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:41][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:42])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[C:38]([CH3:40])[N:37]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from [2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(isopropyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M307) (0.43 g, 0.72 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (310 mg, 90%).
Reaction SMILES: CC1[N:3]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14]4[N:15]3[CH:18]([CH3:23])[C:19](=[O:22])[NH:20][N:21]=4)=[CH:10][CH:9]=2)C(C)=CC=1.C(N(CC)CC)C.Cl.NO>CCO.O>[NH2:3][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14]3[N:15]2[CH:18]([CH3:23])[C:19](=[O:22])[NH:20][N:21]=3)=[CH:10][CH:9]=1
Reactant: Cc1ccc(C)n1-c1ccc2c(c1)N1C(=NNC(=O)C1C)CC2
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1C(=O)NN=C2CCc3ccc(N)cc3N21
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a solution of 9-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one (0.140 g, 0.45 mmol) and triethylamine (0.138 g, 1.362 mmol) in EtOH (9 mL) was added a solution of hydroxylamine hydrochloride (0.095 g, 1.362 mmol) in water (3 mL) and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50-100% EtOAc in petroleum ether) to give 9-amino-1-methyl-5,6-dihydro-1H-[1,2,4]-triazino[4,3-a]quinolin-2(3H)-one (0.070 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.06 (brs, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.0 HZ, 1H), 6.26 (s, 1H), 4.60 (q, J=6.8 HZ, 1H), 3.63 (brs, 2H), 2.67 (m, 2H), 2.53 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:18]1([CH:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][N:26]([CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])[CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][CH2:27][N:26]([CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:9](=[O:11])[CH:8]=[CH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:25]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NCCCCN1CCc2ccccc2C(c2ccccc2)C1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
Batch size: 2.8 g (18.8 mmol) 3-(3-Pyridyl)-acrylic acid, 2.2 ml (25.5 mmol) oxalyl chloride and 5.0 g (17.0 mmol) 4-(1-phenyl-1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-butylamine.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:55][CH2:56][N:57]2[CH2:62][CH2:61][C@H:60]([OH:63])[C@@H:59]([CH3:64])[CH2:58]2)CC1>>[ClH:1].[ClH:1].[OH:63][C@H:60]1[CH2:61][CH2:62][N:57]([CH2:56][CH2:55][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:58][C@@H:59]1[CH3:64]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119, see example 80) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>C(OCC)C>[CH2:1]([C:3]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH2:5][OH:6])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C=O
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCc1cc(C)cc(CC)c1CO
Yield: 92.2 %

Procedure:
A solution of 35.5 g (201.4 mmol) of 2,6-diethyl-4-methylbenzaldehyde, dissolved in 80 ml of diethyl ether is added dropwise to a suspension of 2.10 g (55.4 mmol) of lithium aluminium hydride in 200 ml of diethyl ether. The mixture is then heated at reflux for another 1 h. After cooling, the mixture is hydrolyzed with water and 10% strength sulphuric acid, the phases are separated and the aqueous phase is extracted two more times with diethyl ether. Drying (magnesium sulphate), distillative removal of the solvent and chromatography of the resulting crude product on silica gel (ethyl acetate/hexane=30:70) gives 33.10 g (92%) of 2,6-diethyl-4-methylbenzyl alcohol in the form of colourless crystals of m.p. 71-72° C. 1H-NMR (400 MHz, CDCl3): δ=1.22 (t, 6H), 2.30 (s, 3H), 2.74 (q, 4H), 4.71 (s, 2H), 6.90 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]1[C:9]([O:11][CH3:12])=[O:10].[S:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.B(F)(F)F.C([Li])CCC.[OH-].[Na+]>C1COCC1.CC(OC)(C)C>[OH:8][C@:6]1([C:15]2[S:14][CH:18]=[CH:17][N:16]=2)[CH2:5][CH2:4][C@H:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]([CH3:13])([CH3:1])[CH2:7]1
Reactant: COC(=O)[C@H]1CCC(=O)CC1(C)C
Reactant: c1cscn1
Agent: FB(F)F
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)[C@H]1CC[C@](O)(c2nccs2)CC1(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl(1S)-2,2-dimethyl-4-oxocyclohexanecarboxylate (10 g, 54.28 mmol)) in THF (16.3 g) was added additional THF (184 mL) followed by thiazole (6.93 g, 81.42 mmol). The resulting solution was then cooled to −78° C. Boron trifluoride diethyletherate (9.24 g, 65.14 mmol) was added over 24 minutes and the resulting mixture aged at −78° C. for 5 minutes. n-Butyllithium (2.5M in hexanes, 20.05 g, 71.98 mmol) was added to the mixture subsurface over 4 hours and the mixture was aged for 15 mins. Sodium hydroxide (1M aqueous solution, 54.3 mL, 54.3 mmol) was added followed by MTBE (54 mL) and the mixture was warmed to 20° C. The aqueous layer was separated and the organic layer was washed with a half saturated aqueous solution of sodium chloride (54 mL) resulting in a light yellow solution of methyl(1S,4R)-4-hydroxy-2,2-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate, which was then concentrated under partial vacuum to a low volume. Methanol (124 mL) was added and the solution concentrated to an oil under partial vacuum. The solution was then diluted with methanol (124 mL) and heated to 40° C. A solution of 1M sodium hydroxide (92 mL, 92.0 mmol) was added over 5 minutes and the resulting mixture heated to 50° C. then aged for 16 hours before being cooled to 20° C. The solution was washed three times with dichloromethane (124 mL, 62 mL, 62 mL) and the aqueous methanol solution of the product was crystallised by addition of GM aqueous HCl (15.3 mL, 92 mmol) over 30 mins. The slurry was aged for 2 hours then the mixture was concentrated under partial vacuum to a total volume of 124 mL. The solid was collected by filtration and washed with water-methanol (1:1 v:v, 62 mL) then water (62 mL) to give the title compound (11.44 g, 41.86 mmol, 99.9% ee) as a pale yellow solid. MS ESI: [M+H]+ 256.1 NMR (400 MHz, DMSO-d6): 11.89-12.09 (br s, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.53 (d, J=3.5 Hz, 1H), 5.79 (s, 1H), 3.36 (br s, 2H), 2.13-2.20 (m, 2H), 1.95-2.09 (m, 1H), 1.76-1.91 (m, 3H), 1.53-1.65 (m, 2H), 1.11 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8](=O)[CH3:9].[O-]S([O-])(=O)=O.[Mg+2].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH:8](=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])\[CH3:9]
Reactant: CC=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flask (S)-2-methyl-propane-2-sulfinic acid amide (1.50 g, 12.4 mmol) was dissolved in CH2Cl2 (6 mL). Acetaldehyde (6.25 mL, 111 mmol), MgSO4 (4.47 g, 37.1 mmol) and pyridinium tosylate (156 mg, 0.62 mmol) were added. The reaction mixture was stirred overnight at room temperature, filtered and concentrated to give (S)-2-methyl-propane-2-sulfinic acid (E)-ethylideneamide as a pale red oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][NH:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:24]([CH3:23])[CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CNCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N(C)CCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N-methyl-N′-(2-pyridyl)-1,2-ethanediamine (326 mg, 2.16 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. Triethylamine (0.300 mL, 2.15 mmol) was added and the mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL), the resulting precipitate was collected by filtration, washed with water and dried to give 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[methyl[2-(2-pyridylamino)ethyl]amino]-4-oxoquinoline-3-carboxylic acid (392 mg, 62%) as a yellow solid.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].[F:34][CH2:35][CH:36](O)[CH2:37][F:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:34][CH2:35][CH:36]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:37][F:38]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: OC(CF)CF
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Reaction time: 48 h
Yield: 113.6 %

Procedure:
DIAD (7.63 mL, 38.7 mmol) was added in a dropwise fashion to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (5.00 g, 19.4 mmol), 1,3-difluoropropan-2-ol (3 mL, 38.7 mmol), and triphenylphosphine (10.16 g, 38.7 mmol) in THF (100 mL) under an inert atmosphere at 0° C. The solution was allowed to reach RT and left to stir for 2 days. The THF was removed in vacuo and the residual oil slurried with a mixture of 20% ethyl acetate in isohexane. After allowing to stir for 90 minutes the mixture was filtered and the filtrate evaporated. The residual was oil chromatographed on silica, eluting with 30% ethyl acetate in isohexane, to give the desired compound (7.41 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[O:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[C:18](O)=[O:19].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18]([C@@H:14]3[CH2:15][CH2:16][CH2:17][O:13]3)=[O:19])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)[C@@H]1CCCO1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1CCCO1
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.8 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol), (S)-tetrahydrofuran-2-carboxylic acid (252 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP—Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 7 hours. 2M LiOH (5 mL) was added then to the mixture and stirred at room temperature for 30 minutes. Water (25 mL) was then added and stirred for an additional 30 minutes. The solid formed was filtered, washed with water (3×5 mL) and dried to provide (S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (202 mg, 70.8% yield) as a solid. LCMS (APCI+) m/z 327.9, 329.9 (M+H)+; Retention time=2.80 minutes (Method 2).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1>Br>[O:2]=[C:3]1[NH:8][CH:7]=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4]1
Reactant: COc1ccc(C=O)cn1
Agent: Br
Product: O=Cc1ccc(=O)[nH]c1
Temperature: 25 °C
Yield: 121.5 %

Procedure:
6-Methoxy-pyridine-3-carbaldehyde (1.0 g, 7.29 mMol) was dissolved in hydrobromic acid (14 mL, 48% in water) and the resulting solution heated to 150 degrees gradually over one hour. The solution was then cooled to room temperature and concentrated to dryness on a rotary evaporator. Methanol (4 mL) and acetone (2 mL) were added and the solution washed with diethyl ether (3×15 mL). Water (10 mL) was added and the pH adjusted to neutral with sodium bicarbonate. The solution was then filtered and concentrated to dryness on a rotary evaporator to yield a tan solid. Purification by flash column chromatography on silica gel using 30% methanol in chloroform as eluant yielded 1.09 g (73% yield ) of 6-Oxo-1,6-dihydro-pyridine-3-carbaldehyde as a hydrobromide salt. 1H NMR (DMSO-d6): δ=12.30 (br s, 1H), 9.60 (s, 1H), 8.26 (m, 1H), 7.75 (dd, 1H, J=9.5, 2.6Hz), 6.41 (d, 1H, J=9.5 Hz). LC/MS (Method A), rt=0.25 mins., purity=98%, calculated mass=123,[M−H]−=122. HPLC (Method C): rt=1.76 mins., purity=91.2% @ 210-370nm and 91.5% (286 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])=[O:30])=[CH:19][N:20](COCC[Si](C)(C)C)[C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:29]([NH:31][CH:32]([CH2:33][OH:34])[CH2:35][OH:36])=[O:30])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(CO)CO)c3n2)c2ccc(Cl)cc21
Reaction time: 18 h
Yield: 33.3 %

Procedure:
To a stirred solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.035 g, 0.066 mmol) in dichloromethane (3 mL) was added TFA (0.38 g, 0.25 mL, 3.3 mmol) at 20° C. After 18 h, the mixture was concentrated in vacuo. The residue was diluted with dichloromethane and concentrated again. The residue was then suspended in dichloromethane (3 mL) and ethylenediamine (0.2 g, 0.22 mL, 3.3 mmol) added. The mixture was stirred for 3 h, then concentrated in vacuo. The residue was collected by filtration and purified by HPLC eluting with MeCN/water (20-95%) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1,3-dihydroxypropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (0.009 g, 0.022 mmol, 34%) as a white powder. MS (M+H)+=401; 1H NMR (DMSO-d6) δ: 12.86 (br. s., 1H), 9.15 (s, 1H), 8.73 (d, J=8.5 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.93-5.02 (m, 2H), 4.17 (s, 4H), 3.56-3.77 (m, 4H).