Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[S:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:15]=2[OH:33])=[CH:3][CH:2]=1.C(Cl)Cl.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46]>O>[C:44]([O:33][C:15]1[CH:16]=[CH:17][C:18]([C:20]2[C:25]3[S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:19][C:14]=1[C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)(=[O:47])[CH:45]=[CH2:46]
Reactant: Oc1ccc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1.02 g of the thus obtained 2,4-bis(4-dibenzothiophenyl)phenol is placed in a round bottom flask; 5 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.27 g of triethylamine is added; 0.24 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and then gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=80/20 (volume ratio)) to concentrate a component having an Rf of 0.42, thereby obtaining 1.0 g (yield: 88%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 6.05 (dd=1.2 & 10.4 Hz, 1H), 6.37 (dd=10.4 & 17.2 Hz, 1H), 6.66 (dd=1.2 & 17.2 Hz, 1H), 7.30 to 8.25 (m, 17H)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:43]=[O:44].Cl>O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([CH:43]=[O:44])=[CH:7][C:6]=3[C:5]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:13][CH:14]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of 2,7-dibromo-9,9-didecylfluorene (95.5 g, 0.158 mol) in terahydrofuran (THF, 375 mL), cooled In a dry-ice acetone bath, a 1.6 M solution of n-butyl lithium in hexanes (100 mL) was added over a period of 25 minutes. After stirring for 30 minutes a solution of dimethylforamide (DMF, 23 mL) in THF (25 ml) was added and the mixture was stirred for 1 hour in the cooling bath. After the mixture had been warmed to 0° C., hydrochloric acid (1:1, 50 mL) was added, diluted with toluene and the organic phase was separated, dried and concentrated. The residue that remained after rotary evaporation of the solvents was chromatographed over 600 g of silica gel. After elution with hexanes, the column was eluted with 1:3 toluene-hexane to obtain the aldehyde, 70.5 g, (81% yield), m.p. 45-47° C. A sample was recrystallized from a mixture of isopropanol and methanol, m.p. 49-49.5° C. IR (KBr; cm−1): 2922, 2853, 1696 (C═O), 1605, 1459. Anal. Calcd. for C34H49BrO: C, 73.76%; H, 8.92%; Br, 14.43%. Found: C, 73.75%; H, 8.86%; Br, 14.64%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2.Cl[CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[F:20][C:4]([F:19])([F:3])[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2
Reactant: ClCc1nccs1
Reactant: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(F)(F)F)ccc2n1Cc1nccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a suspension of 87 mg (1.983 mmol) of sodium hydride (55%) in 10 mL of dry DMF, maintained under an inert atmosphere, are added dropwise, at room temperature, 340 mg (1.322 mmol) of ethyl 5-trifluoromethyl-1H-indole-2-carboxylate in 5 mL of dry DMF. The reaction mixture is stirred at 50° C. for 1 hour. A solution of 265 mg (1.983 mmol) of 2-(chloromethyl)thiazole, prepared according to the protocol described in the preceding step, in 10 mL of THF is then added dropwise, at 0° C. The reaction mixture is then stirred for 20 hours at room temperature, and then diluted with 100 mL of ethyl acetate. The aqueous phase is extracted with 30 mL of ethyl acetate. The combined organic phases are washed successively with saturated aqueous sodium hydrogen carbonate solution, with water, with saturated aqueous sodium chloride solution and then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting oil is purified by chromatography on a column of silica, eluting with a mixture of heptane and ethyl acetate. 265 mg of the expected product are isolated in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry N,N-dimethylforuiamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[N:25]=[N:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Reactant: N#Cc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nn1
Temperature: 120 °C
Yield: 7.1 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloropyridazine-3-carbonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor (250 psi maximum pressure, 1 min ramp, 300 max watts). The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)pyridazine-3-carbonitrile (0.016 g, 24%): LC/MS (Table 2, Method a) Rt=1.76 min; m/z: 345 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13]C[CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(OC[C@@H]2CCN2C(OC(C)(C)C)=O)(=O)=O)=CC=1>>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:11][N:10]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1ccccc1
Yield: 79 %

Procedure:
(S)-tert-Butyl 2-(phenoxymethyl)azetidine-1-carboxylate (16) was prepared according to the same procedure for compound 9, except using compound 15, and purified with hexanes-ether (2:1) to afford 0.81 g (79%) of 16 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ CDCl3 7.30 (m, 2H), 6.94 (m, 3H), 4.53 (m, 1H), 4.26 (m, 1H), 4.12 (m, 1H), 3.93 (m, 2H), 2.33 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[CH3:16].Cl>C(O)(=O)C>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][C:13]2[CH:3]=[CH:4][NH:5][C:6](=[O:17])[CH2:7][C:8]=2[C:9]=1[CH3:16]
Reactant: COc1cccc(CC(=O)NCC(OC)OC)c1C
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc2c(c1C)CC(=O)NC=C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of N-(2,2-dimethoxy-ethyl)-2-(3-methoxy-2-methyl-phenyl)-acetamide (23 g) in a mixture of acetic acid (40 ml) and conc. HCl (40 ml) was stirred at room temperature for 24 hours. Ice was added with vigorous stirring and the obtained precipitated was filtered (10.9 g, 62% yield).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=O.[NH2:19][C:20]1[CH2:24][CH2:23][CH2:22][N:21]=1.O>CN(C)C=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:19]=[C:20]3[CH2:24][CH2:23][CH2:22][N:21]3[C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC1=NCCC1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2nc3n(c2-c2ccc(Cl)cc2)CCC3)cc1

Procedure:
A mixture of 6.2 g (0.018 mol) of 2-bromo-1,2-di-(4-chlorophenyl)ethanone and 4.6 g (0.054 mol) of 2-amino-4,5-dihydro-3H-pyrrole in 60 ml of dry N,N-dimethylformamide was stirred at 25° with exclusion of water for five days. The mixture was then poured into water and the aqueous solution was extracted three times with methylene chloride. The extracts were combined and washed eight times with water, dried (K2CO3) and evaporated. The residue was chromatographed on silica gel (dry column) with 1% tetrahydrofuran in chloroform and 5% tetrahydrofuran in chloroform as eluants. The product-containing section was washed with methanol to remove the product which was, after evaporation of the methanol, recrystallized from methanol-water to give the title compound, m.p. 189°-192°.
Reaction SMILES: ClC1C=CC=CC=1C(NC1C=CC2CCC3C(C(N)=O)=[N:15][N:16]([C:18]4[CH:23]=[CH:22][C:21]([S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=4)C=3C=2C=1)=O.N#N.NN>C(O)C>[CH:27]([S:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:16][NH2:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25])([CH3:29])[CH3:28]
Reactant: CC(C)S(=O)(=O)c1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Agent: N#N
Agent: NN
Solvent: CCO
Product: CC(C)S(=O)(=O)c1ccc(NN)cc1
Yield: 38.2 %

Procedure:
The product of step 1 (640 mg, 3.15 mmol) was dissolved in absolute ethanol (12 mL), the system was flushed with N2 and hydrazine (404 mg, 12.6 mmol) was added and the reaction refluxed overnight. HPLC showed 78% product and 21% starting material. To drive the reaction to completion 2 equivalents of additional hydrazine was added and reaction was refluxed for additional 5 hours, at this time HPLC indicated 95% product. The reaction mixture was concentrated and the residue was stirred with water. A white solid, 390 mg (58%) was isolated. HPLC indicated 86% product and 14% starting material. The aqueous phase was extracted with ethyl acetate (3×50 mL). The organic phase was dried over MgSO4, and concentrated to yield 258 mg (38%) of 1-[4-(isopropylsulfonyl)phenyl]hydrazine with 99% purity. MH+=215. The 390 mg was re-dissolved in 10 mL ethanol and treated once more with additional hydrazine to obtain additional product with the desired purity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[C:29]([CH3:33])([CH3:32])[CH:30]=[O:31].CC(C)=[O:36]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:16])[NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[C:29]([CH3:33])([CH3:32])[C:30]([OH:36])=[O:31]
Reactant: CC(C)(C=O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reactant: CC(C)=O
Product: CC(C)(C(=O)O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Reaction time: 1 h
Yield: 5 %

Procedure:
To a solution of crude (±)-7-bromo-N-(2-adamantyl)-3-(2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (40 mg, 0.0778 mmol) in dry acetone was added H2Cr2O7 (234 mg, 0.8 mmol), and the solution was stirred for 1 h. 0.5 Treatment of the mixture with NaBH4 and concentration afforded the crude product which was purified by preparative HPLC to give (±)-2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoic acid (1.55 mg, 5%). LC-MS Method 5 tR=1.504 min, m/z=531; 1H NMR: (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43 (m, 2H), 1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H), 2.51-2.61 (m, 1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m; 2H), 7.01 (m, 1H), 7.21-7.33 (m, 2H).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]1[N:34]=[CH:33][C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:21]([CH3:32])[CH:20]=3)[C:12]=2[CH:11]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]1([C:6]([N:29]2[CH2:28][CH2:27][CH:26]([O:25][C:22]3[CH:23]=[CH:24][C:19]([NH:18][C:17]4[C:12]5[CH:11]=[C:10]([F:9])[N:34]=[CH:33][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:20][C:21]=3[CH3:32])[CH2:31][CH2:30]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCNCC1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Yield: 69.5 %

Procedure:
Cyclopentane carbonyl chloride (0.187 g, 1.41 mmol) was added to a solution of (6-Fluoro-pyrido[3,4-d]pyrimidin-4-yl)-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-amine (T) (0.50 g, 1.28 mmol) and NEt3 (0.38 g, 3.84 mmol) in CH2Cl2 (15 mL After 1 h the reaction was quenched with water, the layers were separated and the organic layer was washed with 1N NaOH and water, dried over Na2SO4, and concentrated. Purification by flash column chromatography (CH2Cl2/MeOH, 97/3) afforded the title compound as a yellow solid (0.40 g, 70%). LRMS: 450.3 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 9.90 (s, 1H), δ 8.86 (s, 1H), δ 8.58 (s, 1H), δ 8.19 (s, 1H), δ 7.54-7.56 (m, 2H), δ 7.04 (d, J=9.56 Hz, 1H) δ 4.58-4.61 (m, 1H), δ 3.70-3.72 (m, 2H), δ 3.33-3.44 (m, 2H), δ 2.93-3.008 (m, 1H), δ 2.17 (s, 3H), δ 1.46-1.94 (m, 12H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CC(N(C)C)=O.CS(C)=O>[CH:28]([O:27][C:25](=[O:26])[NH:23][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:30])[CH3:29]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCOCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCOCC2)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.08 g, 0.253 mmol) in 2.0 mL of DMA was added isopropyl chloroformate (0.034 g, 0.278 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and was subjected to purification on RP-HPLC. The proper fractions were collected and lyophilized to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester as an off-white semisolid in 80% yield. LCMS m/z (%)=403 (M+H, 100). 1H NMR (400 MH, Acetone-d6) δ: 8.35 (bs. 1H), 7.45 (dd, J=8.4 and 2.6 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.95 Hz, 1H), 6.05 (d, J=1.82 Hz, 1H), 4.69-4.76, (m, 1H), 4.31 (t, J=4.36 Hz, 2H), 3.52 (s, 3H), 3.41 (t, J=4.93 Hz, 2H), 3.10-3.30 (m, 4H), 2.71-2.80 (m, 4H), 1.05 (d, J=6.12 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].C(S([C:13]1[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]#[C:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[CH:16][N:17]=1)(=O)=O)C>O1CCCC1>[O:5]1[CH:4]([CH2:6][O:7][C:13]2[S:14][C:15]([C:18]([NH:20][CH2:21][CH2:22][C:23]#[C:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[CH:16][N:17]=2)[CH2:3]1
Reactant: OCC1CO1
Reactant: CCS(=O)(=O)c1ncc(C(=O)NCCC#CC(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C#CCCNC(=O)c1cnc(OCC2CO2)s1
Temperature: -5 °C

Procedure:
In this preparation 0.0525 mole of sodium hydride in a 50% mineral oil mixture is stirred in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, then cooled to -30° C and 0.055 mole of glycidol is added dropwise. The mixture is allowed to warm to -5° C and stirred for 10 minutes and then recooled to -30° C. A solution of 0.05 mole of 2-ethylsulfonyl-5-(5-methylhex-3-ynylaminocarbonyl)thiazole in 100 ml. of anhydrous tetrahydrofuran is added dropwise and the resulting mixture allowed to warm to 0° C. Additional solvent is added as needed to facilitate stirring. The mixture is maintained at 30 minutes at 0° C and then poured into 500 ml. of ethyl acetate, extracted with 100 ml. of water, and then with 100 ml. of aqueous saturated sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under vacuum affording an oily residue which is then further purified by chromatography on silica gel eluting with 40% ethyl acetate-60% hexane, by vol., affording 1,2-epoxy-3-[5-(5-methylhex-3-ynylaminocarbonyl)thiazol-2-yloxy]propane.
Reaction SMILES: Cl[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[OH-].[Na+].[S:12](=[O:15])([OH:14])[O-:13].[Na+]>[Cu]Cl.O>[S:12]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1)([OH:15])(=[O:14])=[O:13]
Reactant: O=C(O)c1cscc1Cl
Reactant: O=S([O-])O
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cscc1S(=O)(=O)O
Temperature: 0 °C

Procedure:
In a glass autoclave, 8.6 g. of 4-chlorothiophene-3-carboxylic acid are dissolved in 23 ml. of water containing 2.1 g. of sodium hydroxide, whereupon a solution of 5.6 g. of sodium bisulfite in 16 ml. of water is added and the solution made just alkaline with a 30% sodium hydroxide solution. The solution is treated with 0.43 g. of copper (I) chloride and heated at 143° C. for 16 hours. After cooling, the red copper oxide is filtered off under suction. The filtrate is acidified with 7 ml. of concentrated hydrochloric acid and the unreacted starting material precipitates out, the latter being removed by shaking out with ether. The acidic solution is treated with 12 g. of potassium chloride while warming and, after cooling to 0° C., the potassium salt of 4-sulfothiophene-3-carboxylic acid separates as colorless crystals. The crystals are dissolved in 50 ml. of water and the solution passed through an ion-exchange column which is charged with protons, after which the column is rinsed with water until the solution flowing out has a pH value of 5. The eluate is evaporated to dryness in vacuo. There is obtained 4-sulfothiophene-3-carboxylic acid as a crystalline residue of melting point 154° C. (recrystallization from water).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH3:12].[CH3:13][NH2:14]>>[NH2:1][C:2]1[C:7]([C:8]([NH:14][CH3:13])=[O:10])=[CH:6][N:5]=[CH:4][C:3]=1[CH3:12]
Reactant: COC(=O)c1cncc(C)c1N
Reactant: CN
Product: CNC(=O)c1cncc(C)c1N
Temperature: 100 °C
Yield: 91 %

Procedure:
Methyl 4-amino-5-methylnicotinate (100 mg, 0.60 mmol) and methylamine (2.0 M in MeOH, 2 mL) were mixed, and stirred under heat at 100° C. in a sealed tube for 24 hours. The solvent was evaporated off under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=9/1) to obtain the intended compound (91 mg, 91%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([Br:12])=[O:11].[Br:13]Br>CCCCCC>[Br:13][CH:9]([C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])[C:10]([Br:12])=[O:11]
Reactant: O=C(Br)Cc1c(Cl)cccc1Cl
Reactant: BrBr
Solvent: CCCCCC
Product: O=C(Br)C(Br)c1c(Cl)cccc1Cl

Procedure:
To 36.0 g (0.134 mols) 2,6-dichlorophenyl acetyl bromide, are added in drops at 160 degrees C., 21.5 g (0.134 mols) bromine over 3 hours, and the resultant mixture is then stirred for another 2 hours at 170 degrees C. While stirring, 100 ml hexane are added at 90 degrees C., followed by suction-filtering of the bromide after cooling.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23](=[O:25])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:34][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([CH2:17][S:18]([N:21]3[CH2:24][C:23]([CH3:34])([OH:25])[CH2:22]3)(=[O:19])=[O:20])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Solvent: C1CCOC1
Product: CC1(O)CN(S(=O)(=O)CC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
To a stirred solution of 1-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-cyclohexylmethanesulfonyl]-azetidin-3-one (Example 31) (58 mg, 0.11 mmol.) in tetrahydrofuran (5 mL) was added a solution of methyl magnesium bromide (3M in diethyl ether, 0.075 mL, 0.22 mmol.) and the mixture stirred at ambient temperature for 45 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (10 mL) and the mixture extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with ethyl acetate:dichloromethane:iso-hexane (1:1:1), to afford the desired product (51 mg).