Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]=[O:42])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:43][CH:44]([CH3:49])[C:45]#[C:46][Mg]Br.C([Mg]Br)C.CC(C)C#C.C([Mg]Br)#C>C1(C)C=CC=CC=1>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:22](=[O:23])[C:17]=4[C:16]=3[CH:41]([OH:42])[C:46]#[C:45][CH:44]([CH3:49])[CH3:43])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CC(C)C#C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(C=O)c(-c3ccc(OC(F)F)c(OC4CC4)c3)n2COCC[Si](C)(C)C)c1=O
Agent: C#CC(C)C
Agent: C#C[Mg]Br
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Product: CC(C)C#CC(O)c1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 67 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 71-(a) except for using 1.74 g (2.80 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-formyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the same manner as in Example 15-(a), and using 6 ml of toluene solution containing 27w % 27 wt % 3-methyl-1-butynyl magnesium bromide prepared from ethyl magnesium bromide and 3-methyl-1-butyne in place of tetrahydrofuran solution containing ethynyl magnesium bromide, whereby 1.30 g of the title compound was obtained as a white foam. (Yield: 67%)
Reaction SMILES: Cl[C:2]1[CH:27]=[C:26]([CH3:28])[C:5]([C:6]([NH:8][CH2:9][CH2:10][C@H:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)[CH2:15][CH2:14]2)[CH3:12])=[O:7])=[C:4]([CH3:29])[N:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>COCCOC.C(Cl)Cl.C([O-])(O)=O.[Na+].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>[S:23]1[CH:24]=[CH:25][C:21]([CH2:20][NH:19][CH:16]2[CH2:17][CH2:18][N:13]([C@H:11]([CH3:12])[CH2:10][CH2:9][NH:8][C:6]([C:5]3[C:26]([CH3:28])=[CH:27][C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)=[N:3][C:4]=3[CH3:29])=[O:7])[CH2:14][CH2:15]2)=[CH:22]1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cc(-c2cccnc2)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To an argon-degassed solution of 6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (100 mg, 0.23 mmol) and 3-pyridine boronic acid (56 mg, 0.46 mmol) in DME/2 M Na2CO3 (5:2, 3.5 ml) was added Pd(PPh3)4 (15 mg, 0.013 mmol) and the reaction stirred at 90° C. overnight. The mixture was cooled, diluted with CH2Cl2 (25 ml) and saturated aqueous NaHCO3 (25 ml). The aqueous layer was extracted with CH2Cl2 (2×10 ml) and the combined organic extracts were dried (Na2SO4), concentrated and purified by column chromatography on silica gel (CH2Cl2MeOH/NH4OH, 96:4:0 then 88:10:2) to afford 4,6-dimethyl-[2,3′]bipyridinyl-5-carboxylic acid ((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide as a mixture of product and starting amine (˜25%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=[C:16]([CH2:17][CH3:18])[C:3]=12.Cl.C([OH:28])C>>[CH2:17]([C:16]1[C:3]2[C:2](=[O:28])[C:11]3[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=3)[NH:5][C:4]=2[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:15]=1)[CH3:18]
Reactant: CCO
Reactant: CCc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Agent: Cl
Product: CCc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 4-chloro-3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.49 g, 7.22 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL, 36.0 mmol) was added and the mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and recrystallized from ethanol to give the title compound (1.73 g, 73% yield).
Reaction SMILES: [C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][OH:21])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([C:35]1[CH:36]=[CH:37][C:38]([N+:48]([O-:50])=[O:49])=[C:39]([CH:41]([CH3:47])[CH2:42][O:43][C:44](Cl)=[O:45])[CH:40]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[C:11]2[N:12]=[CH:13][N:14]([C:23]=2[N:24]=[CH:25][N:26]=1)[C@@H:15]1[O:22][C@H:19]([CH2:20][O:21][C:44]([O:43][CH2:42][CH:41]([C:39]2[CH:40]=[C:35]([C:27](=[O:34])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:36]=[CH:37][C:38]=2[N+:48]([O-:50])=[O:49])[CH3:47])=[O:45])[C@@H:17]([OH:18])[CH2:16]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Reactant: CC(COC(=O)Cl)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(COC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O)c1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 56.6 %

Procedure:
N6-benzoyl-2′-deoxyadenosine (23.63 g, 67 mmol) was dried by coevaporation with abs. pyridine (3×100 mL), dissolved in pyridine (400 mL) and cooled to 0° C. A solution of 2-(5-benzoyl-2-nitrophenyl)-1-propyl oxycarbonylchloride (19f) (35 mmol, prepared from 10.00 g of alcohol 4f) in abs. CH2Cl2 (100 mL) was added drop wise over a period of 2.5 hours. After stirring over night at ambient temperature the reaction mixture was concentrated in vacuo, dissolved in CH2Cl2 and washed with water (2×200 mL). Excess N6-benzoyl-2′-deoxyadenosine precipitated as a crystalline solid from the aqueous phase and was recovered by filtration. The organic phase was diluted with toluene (100 mL), concentrated in vacuo and purified by silica column chromatography (315 g silica, column diameter 5.5 cm, gradient: CH2Cl2 to CH2Cl2/methanol 100:5) to provide 13.20 g (19.8 mmol, 57%) of the product 29 as a slightly yellow foam. 1H-NMR (250 MHz, DMSO-d6): δ 11.02 and 11.01 (2 s, 2H, NH), 8.67 (s, 1H, H—C(2)), 8.51 and 8.50 (2 s, 2H, H—C(8)), 8.00-7.48 (m, 13H, arom.), 6.46 (m, 1H, H—C(1′)), 5.47 (d, 1H, HO—C(3′)), 4.46 (m, 1H, H—C(3′)), 4.28 (m, 4H, 2×CH2), 4.03 (m, 1H, H—C(4′)), 3.50 (m, β-CH), 2.86 (m, 1H, H—C(2″)), 2.40 (m, 1H, H—C(2′)), 1.28 (d, 3H, γ-CH3).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][NH:19][CH2:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: c1ccc(Cn2c3c(c4ccccc42)CCNC3)cc1

Procedure:
A solution of 9-benzyl-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]-indole (3.66 g, 10.1 mmol) in chloroform (50 ml) was stirred with trifluoroacetic acid (20 ml) at room temperature for 2 hours. The mixture was evaporated to dryness and the residue partitioned between chloroform and saturated potassium carbonate solution (150 ml/1:2). The organic layer was separated and dried (MgSO4). Filtration and evaporation of the solvent gave the product. (2.66 g, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5]Br)(=[O:3])[CH3:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[NH:23][C:24]([C:26]2[N:27]=[N:28][N:29]([OH:31])[CH:30]=2)=[O:25])=[CH:17][CH:16]=1.CC(C)=O.CCN(CC)CC>>[C:1]([O:4][CH2:5][O:31][N:29]1[CH:30]=[C:26]([C:24]([NH:23][N:22]([CH2:32][C@@H:33]([OH:37])[C:34]([OH:36])=[O:35])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:9]3[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=3[Cl:7])=[CH:16][CH:17]=2)=[O:25])[N:27]=[N:28]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCBr
Reactant: O=C(NN(Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C[C@@H](O)C(=O)O)c1cn(O)nn1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCOn1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3Cl)cc2)C[C@@H](O)C(=O)O)nn1
Temperature: 55 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
Bromomethyl acetate (15.3 mg, 100 μmol) was added to a solution of (R)-3-[N-(2′,5′-dichlorobiphenyl-4-ylmethyl)-N′-(1-hydroxy-1H-1,2,3-triazole-4-carbonyl)hydrazino]-2-hydroxypropionic acid (31.2 mg, 66.8 μmol) in acetone (0.5 mL, 6.8 mmol) followed by Et3N (18.6 μL, 134 μmol). The resulting mixture was stirred at 55° C. for 1 hour. The mixture was then concentrated in vacuo to yield a yellow liquid. The crude liquid was purified (preparative scale C18 column chromatography, small column, using 30-90% MeCN in water with 0.05% TFA) to yield the title compound (5.2 mg, purity 96%) as a white solid. MS m/z [M+H]+ calc'd for C22H21Cl2N5O2, 538.08. found 538.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([CH:29]2[NH:34][C:33](=[O:35])[CH:32]([CH2:36][CH2:37][CH2:38][OH:39])[O:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[CH:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:30][O:31][C@H:32]([CH2:36][CH2:37][CH2:38][OH:39])[C:33]1=[O:35])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Reactant: O=C1NC(C2CCCCC2)COC1CCCO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@@H](CCCO)OCC1C1CCCCC1
Temperature: 110 °C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
A 10 mL heavy wall vial was charged with trans-cyclohexane diamine (11.8 mg, 0.10 mmol, 0.5 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (125 mg, 0.41 mmol, 2.0 equiv), K2CO3 (57 mg, 0.41 mmol, 2.0 equiv), CuI (19.7 mg, 0.10 mmol, 0.5 equiv), 5-cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one (50 mg, 0.21 mmol, 1.0 equiv) and 1,4-dioxane (0.5 mL). The mixture was flushed with N2 and stirred at 110° C. for 24 hours. The mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel, EtOAc/heptane 30% to give product 10 mg (yield 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][N:20]4[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH2:18][CH:19]4[CH2:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][N:20]4[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CC(F)(F)CCN4C(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 2-[[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]methyl]-4,4-difluoro-piperidine-1-carboxylate, 13j, (0.23 g, 0.35 mmol) in methanol (4 mL) was added sodium methanolate (4 mL of 25% w/v, 18.51 mmol). The reaction mixture was allowed to stir at room temperature for 15 minutes. All volatiles were removed at reduced pressure and the residue was quenched with water. EtOAc was added and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was pure enough to be used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[CH3:24][O:25][C:26](=[O:42])[C:27]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl.CCCCCC.CCOC(C)=O.CN(C=O)C>[CH3:24][O:25][C:26](=[O:42])[C:27]([CH3:41])([O:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:28][C:29]1[S:30][C:31]([C:15](=[O:17])[CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:32][CH:33]=1
Reactant: COC(=O)C(C)(Cc1cccs1)Oc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)(Cc1ccc(C(=O)CCc2nc(-c3ccccc3)oc2C)s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
A sample of 3-(5-methyl-2-phenyl-oxazol-4-yl)-propionic acid (2.27 g, 9.82 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) followed by addition of a catalytic amount of DMF (0.72 mL) and slow addition of a 2 M solution of oxalyl chloride (7.36 mL). The reaction mixture was stirred at room temperature for 24 h under N2. The solvent was removed in vacuo to provide crude acid chloride which was then dissolved in 10 mL anhydrous CH2Cl2 and then added to a flask containing 2-methyl-2-phenoxy-3-thiophen-2-yl-propionic acid methyl ester (527167) (2.51 g, 9.11 mmol) in anhydrous CH2Cl2 (10 mL) at 0° C. under N2. Anhydrous 1.0 M SnCl4 solution (5.6 mL) was then added dropwise at 0° C. After 1 h, the reaction was checked by HPLC, it appeared that little product had formed. Another 3.3 mL of SnCl4 solution was added and allowed to stir for 24 h at room temperature. When the starting materials were consumed, the reaction was quenched by adding 6 M HCl dropwise at 0° C. until solid forms (20 mL) and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with water (50 mL) and solvent removed to give an oil. Following column chromatography (gradient 5% to 20% EtOAc in hexane), 1.31 g (30%) of product was obtained: 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2 H), 7.56 (d, 1 H), 7.38 (m, 3 H), 7.20 (m, 2 H), 6.84 (t, 1 H), 6.81 (m, 3 H), 3.72 (s, 3 H), 3.50 (d, 1 H), 3.33 (d, 1 H), 3.28 (t, 2 H), 2.89 (t, 2 H), 2.33 (s, 3 H), 1.41 (s, 3 H); MS (EI) 490.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(Br)ccc1F
Yield: 67.4 %

Procedure:
Add 4-bromo-1-fluoro-2-nitrobenzene (19.4 g, 88.2 mmol) and 10 g of fine mesh iron to a solution of acetic acid (75 mL) and water (5 mL) and heat to 105° C. for 4 h or until the 4-bromo-1-fluoro-2-nitrobenzene is completely consumed. Concentrate to remove most of the acetic acid, pour into water and extract with ethyl acetate. Wash the ethyl acetate layers with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with hexanes:ethyl acetate, to give the title compound as an amber oil (11.3 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]1[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:7]1=[C:6]([C:27]([O:29]CC)=[O:28])[C:5]2=[O:32].[OH-].[K+].C(O)(C)(C)C.O.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]1[CH:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:20][C:7]1=[C:6]([C:27]([OH:29])=[O:28])[C:5]2=[O:32]
Reactant: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)C(c1ccccc1)S2
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Solvent: O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)c2n3C(c3ccccc3)S2)CC1
Temperature: 50 °C

Procedure:
Three grams of ethyl 6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1-phenyl-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate was suspended in 30 ml of mixed solution of 5% potassium hydroxide/tert-butanol-water (75:25) and the suspension was heated at 50° C. for 4 hours with stirring. To this was added 30 to 40 ml of water to prepare homogeneous solution. The solution was neutralized with acetic acid and extracted with chloroform to which small amount of methanol was added. The extract was dried, concentrated, and the resulting residue was recrystallized from ethanol to give desired product. Yield: 2.23 g. M.p. 216°-217° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:21][N+:18]([O-:20])=[O:19])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
In a 1 l. r.b. flask 100 g. (0.6 mole) of 3,4-dimethoxybenzaldehyde, 40 g. (0.52 mole) of ammonium acetate, 50 ml. (0.93 mole) of nitromethane, and 400 ml. of glacial acetic acid were combined and refluxed for 2 hours. The solution was then cooled to room temperature overnight. Yellow crystals were then collected via suction filtration and washed with hexane and ether. 73 g. of desired product were collected with m.p. 133°-134° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([Cl:12])(=[O:15])=[O:14])[CH:6]=2)[O:1][CH2:2][CH2:3]1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1CCOc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C1CCOc2ccc(S(=O)(=O)Cl)cc21
Temperature: 40 °C

Procedure:
To a solution of 4-chromanone (0.59 g, 4.0 mmol) in CHCl3 (10 mL) was added chlorosulfonic acid (1.0 mL, 15 mmol) and heated to 40° C. for 1 h. After cooling to rt, the solution was poured onto ice and extracted with CH2Cl2 (10 mL). The organic layer was washed with 1 M HCl (3×10 mL) and the combined organic extracts were dried over MgSO4, filtered, and the solvent was removed under reduced pressure to afford 4-oxochroman-6-sulfonyl chloride as a grey solid in quantitative yield. 1H NMR (CD3OD) δ 8.41 (s, 1H), 8.05 (d, 1H), 7.13 (d, 1H), 4.7 (t, 2H), 3.0 (t, 2H).
Reaction SMILES: [NH:1]1CCNCC1.[Cl:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=1>C(#N)C.ClCCl>[Cl:7][C:8]1[C:13]([C:12]#[N:1])=[N:14][CH:11]=[CH:10][N:9]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nccnc1Cl
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Piperazine (1.5 mmol) and 2-chloro-3-nitro-pyridine (1 mmol) were dissolved in acetonitrile (3 mL) and stirred for 30 min at 85° C. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was isolated, washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The product was purified (SPE column chromatography, silica gel, 0-10% methanol in ethyl acetate).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CC[C@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:17]=[CH:16][C:15]=3[OH:32])[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:33](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:33][O:32][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[CH:19][C:14]=1[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH:11]2[CH2:13][CH:8]1[CH2:9][CH2:10]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a solution of 1b (200 mg, 0.47 mmol) in DMF (4 mL) was added cesium carbonate (186 mg, 0.57 mmol) followed by methyl iodide (35.0 μL, 0.57 mmol). The mixture was stirred at room temperature for 18 h, diluted with water (20 mL) and extracted three times with EtOAc. The combined organic extracts were washed three times with water, dried (MgSO4) and concentrated. The residue (210 mg) was triturated with a 1:1 mixture of hexane/ether to provide 1c as a solid (113 mg), m.p. 138-139° C.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@@H:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C@H:10]([CH2:20][CH3:21])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[ClH:22]>O1CCOCC1>[ClH:22].[CH2:20]([C@H:10]1[NH:11][CH2:12][C@@H:8]([NH:7][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])[CH2:9]1)[CH3:21]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)CN1
Temperature: 60 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a solution of (2R,4S)-tert-butyl 4-(cyclopropanesulfonamido)-2-ethylpyrrolidine-1-carboxylate (0.95 g, 2.98 mmol, Preparation #15) in 1,4-dioxane (7.5 mL) was added HCl (4 N in 1,4-dioxane, 7.46 mL, 29.8 mmol). The reaction mixture was heated to about 60° C. After about 4 h, the reaction mixture was cooled to ambient temperature and concd in vacuo to provide crude N-((3S,5R)-5-ethylpyrrolidin-3-yl)cyclopropanesulfonamide hydrochloride (0.38 g, 50%) as a brown residue: LC/MS (Table 1, Method a) Rt=0.63 min; MS m/z: 219 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C1(S(OCC2C(C3SC=CC=3)CCN(C)C2)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]1([S:25]([O:1][CH2:2][CH:3]2[CH:8]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCN1CCC(c2cccs2)C(CO)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1

Procedure:
3-benzenesulphonyloxymethyl-1-pentyl-4-(2-thienyl)-piperidine (14) was prepared from 3-hydroxymethyl-1-pentyl-4-(2-thienyl)piperidine (13 g), benzenesulphonyl chloride (13 ml) and triethylamine (12.5 ml) in dry toluene (100 ml) as described for (2). Yield: 20.4 g, mass spectrum (M+ 407) in accordance with proposed structure