Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)C.[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl.O>[CH3:36][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32]([O:8][CH2:9][CH2:10][NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])(=[O:33])=[O:34]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)OCCNC(=O)OC(C)(C)C)c(C)c1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
Triethylamine (65 mL, 465.3 mmole, 1.5 eq) was added in one portion to a solution of tert-butyl N-(2-hydroxyethyl)carbamate (50.11 g, 310.2 mmole, 1.0 eq.) in dichloromethane (250 mL, 5 vols). The solution was cooled to −10° C. and trimethylamine hydrochloride (14.84 g, 155.1 mmole, 0.5 eq.) was added in one portion. The resultant mixture was cooled further to −15° C., stirred for 5 minutes, then treated with a solution of mesitylenesulfonyl chloride (74.74 g, 341.2 mmole, 1.1 eq) in dichloromethane (250 mL, 5 vols), over 28 minutes such that the internal temperature remained below −10° C. Once the addition was complete a precipitate had formed and the mixture was stirred at −10° C. for a further 30 minutes. Water (400 mL, 8 vols) was added and all of the precipitate dissolved. The mixture was stirred rapidly for 5 minutes, and then the two layers were separated. A solvent swap from dichloromethane to IPA was carried out by distillation at reduced pressure. Solvent was removed (450 mL) and replaced with IPA (450 mL) (initial pressure was 450 mbar, b.p. 24° C.; final pressure was 110 mbar, b.p. 36° C.). At the end of the distillation, solvent (150 mL) was removed to bring the volume down to 350 mL (7 vols with respect to the amount of tert-butyl N-(2-hydroxyethyl)carbamate used). The solution was cooled to 25° C., then water (175 mL) was added slowly with stirring, causing the solution gradually to turn cloudy. No solid had precipitated at this stage. More water (125 mL) was added, and a solid precipitate started to form after about 75 mL had been added. The internal temperature rose from 25° C. to 31° C. The mixture was stirred slowly and cooled to 7° C. The solid was collected by filtration, washed with IPA:water (1:1, 150 mL) and dried in vacuo at 40° C. for 21 hours to give the title compound as a white crystalline solid (92.54 g, 87%).
Reaction SMILES: [ClH:1].[CH:2]1[C:14]2[CH:13]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][C:20]([Cl:22])=[O:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[K+].[K+].Cl>CO.C(OCC)C.ClCCl>[ClH:22].[ClH:1].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[CH2:37][CH2:36][N:35]([C:20](=[O:21])[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:6]4[C:14]3=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH3:23])[CH2:34][CH2:33]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: Fc1ccc(N2CCNCC2)cc1F
Reactant: CN(CCC(=O)Cl)CCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: CN(CCC(=O)N1CCN(c2ccc(F)c(F)c2)CC1)CCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A mixture of 3-{[2-(9H-fluoren-9-yl)-ethyl]-methyl-amino}-propionic acid chloride hydrochloride (1.14 g), 4-(3,4-Difluoro-phenyl)-piperazine (587 mg), dichloromethane (25 ml) and 1 M aq. K2CO3 (25 ml) is stirred at room temperature for 1 hour. The phases are separated, the organic phase dried over sodium sulfate, filtered and evaporated. Purification by chromatography on silicagel (EtOAc/MeOH 7:3) afforded 1.2 g (100%) of a slightly colored oil. It is dissolved in 4 ml MeOH and acidified with 6 ml 1 M HCl in diethyl ether. More ether is added until the solution gets cloudy (ca. 3 ml). Crystallization at 5° afford 1.01 g (74%) of the desired product as dihydrochloride. M.p. 144°-154°. Anal: Calculated. for C29H33Cl2F2N3O.H2O: C, 61.48%; H, 6.22%; N, 7.41%. Found: C, 61.52%; H, 6.36%; N, 7.37%.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(OC1C=CC2C(=CC=CC=2)N1C(OCC)=O)C>O1CCCC1>[C:21]([O:25][C:26]([NH:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[NH:11][C:10]1=[O:20])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1Nc2ccccc2CC[C@H]1NCc1ccccc1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)N(Cc1ccccc1)[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
A solution of 90 mg (0.34 mmol) of 3(R)-(benzylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one in 1.5 mL of tetrahydrofuran under nitrogen at room temperature was treated with 73 mg (0.34 mmol, 1 eq.) of 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) followed by 94 mg (0.38 mmol, 1.1 eq.) of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ). Most of the solvent was evaporated under a stream of nitrogen and the resulting reaction mixture (thick syrup approx. 0.3 mL) was stirred for 3 days. The mixture was evaporated to dryness under vacuum and the residue purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexane (1:1) to afford 45 mg (mmol, 33%) of product. 1H NMR (200MHz, CDCl3): 1.28 (s,3H), 1.32 (s,3H), 1.35 (s,9H), 2.16 (m,2H), 2.35 (d,14Hz,1H), 2.58 (d,14Hz,1H), 2.60 (m,1H), 2.81 (m,1H), 4.70 (d,18Hz,1H), 4.99 (d,18Hz,1H), 5.37 (t,10Hz,1H), 5.83 (br s,1H), 6.98 (d,7Hz,1H), 7.05-7.45 (m,5H), 7.50-7.85 (m,3H), 8.13 (t,8Hz,1H), 8.90 (m,1H). FAB-MS: calculated for C27H35N3O4 465; found 466 (M+H)48%).
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:23]1([NH:29][C:30](=[O:31])[N:3]([CH2:4][C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[CH2:7][N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:9]3=[O:14])[CH3:2])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and cyclohexyl isocyanate (0.28 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and extracted with H2O (40 mL), then with 1N HCl (40 mL). The organic layer was washed with brine (40 mL) and concentrated on rota-vap. The resulting oil was purified on silica gel column to give 3-cyclohexyl-1-[2-(2,6-dioxo-piperidin-3-yl) 1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea (0.54 g, 71%): mp 219-221° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 30/70 (CH3CN/H2O): tR=4.61 (99%); 1H NMR (DMSO-d6): δ 1.02-1.30 (m, 5H), 1.54-1.76 (m, 5H), 2.00-2.05 (m, 1H), 2.29-2.36 (m, 1H), 2.58-2.64 (m, 1H), 2.76 (s, 3H), 2.87-3.01 (m, 1H), 3.36-3.42 (m, 1H), 4.28 (d, J=17.3 Hz, 1H), 4.36 (d, J=17.5 Hz, 1H), 4.53 (s, 2H), 5.12-5.19 (dd, J=4.9, 13.1 Hz, 1H), 6.07 (d, J=7.7 Hz, 1H), 7.38 (d, J=7.4 Hz, 1H), 7.50 (t, J=7.4 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 11.03 (s, 1H). 13C NMR (DMSO-d6) δ: 22.69, 25.10, 25.35, 31.14, 33.22, 34.00, 46.12, 48.21, 49.34, 51.45, 121.59, 128.30, 130.08, 131.87, 134.41, 139.99, 157.09, 168.02, 170.99, 172.84. Anal Calcd for C22H28N4O4+0.1H2O: C, 63.78; H, 6.86; N, 13.52. Found: C, 63.41; H, 6.93; N, 13.33.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[OH:14]OS([O-])=O.[K+].O.Cl>CN(C=O)C.CCOC(C)=O>[CH3:11][O:10][C:8]([C:7]1[CH:12]=[C:3]([CH:4]=[CH:5][C:6]=1[CH3:13])[C:1]([OH:14])=[O:2])=[O:9]
Reactant: O=S([O-])OO
Reactant: COC(=O)c1cc(C=O)ccc1C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 16.75 h

Procedure:
A mixture of 268 mg of the methyl 5-formyl-2-methylbenzoate and 1.08 g (1.76 mmol) of Oxone in 6 mL of DMF was stirred at r.t. for 16.75 h. Water, 1N HCl, and EtOAc were added, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated, and 3-(methoxycarbonyl)-4-methylbenzoic acid, which was used for the next reaction without further purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][O:13][N:14]([CH3:26])[C:15](=[O:25])[C:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17]>C(Cl)Cl>[CH3:12][O:13][N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][Cl:5])=[CH:20][CH:19]=1)([CH3:24])[CH3:17]
Reactant: CON(C)C(=O)C(C)(C)c1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.6 %

Procedure:
Slurry AlCl3 (10.15 g, 76.1 mmol) and methylene chloride (45 mL) under a nitrogen atmosphere at room temperature. Add 4-chlorobutyryl chloride (4.27 mL, 38.1 mmol), stir for minutes and add, by dropwise addition over 10 minutes, a solution of 2-methyl-2-phenyl-propionic acid, N-methoxy-N-methylamide (6.58 g, 31.7 mmol) in methylene chloride (15 mL). Stir at room temperature for 45 minutes, then heat at 30-35° C. for 7 hours. Pour into ice water (150 mL) and separate the layers. Wash the aqueous layer with water (3×75 mL), combine the aqueous layers and extract with methylene chloride (2×75 mL). Combine the organic layers and dry (Na2SO4). Filter, evaporate the filtrate in vacuo and purify by silica gel chromatography (3:1 hexane/ethyl acetate) give the title compound (6.19 g, 63%) as a light yellow oil.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13](=O)[C:14](=[CH:17]OCC)[C:15]#[N:16])C>CN(C=O)C>[OH:12][C:13]1[C:14]([C:15]#[N:16])=[CH:17][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: N=C(N)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2ccccc2)nc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzamidine (1.0 g, 8.32 mmol) in anhydrous DMF (20 mL ) was added Ethyl(ethoxymethylene)cyanoacetate (11) (1.41 g, 8.32 mmol, 1.0 equiv ) under argon at 0° C. The mixture was stirred at 0° C. for 2 h and increase to 105° C. for 60 h. The reaction mixture was then cooled to ambient temperature. The mixture was extracted with ethyl acetate (2×100 mL ). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered, and evaporated in vacuo. The residue was washed with water (1×60 mL), dichloromethane (1×60 mL) then dried in the vacuum oven to obtain the light yellow solid as product (0.77 g, 47%). 1H-NMR (CD3CN) δ8.25 (s, 1H ), 8.06 (d, 2H ), 7.70 (t, 1H ), 7.61 (t, 2H). MS LC-MS (MH+=198).
Reaction SMILES: C([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH2:11])C1C=CC=CC=1.C(N(CC)CC)C.[CH2:26]([O:28][C:29](=[O:33])[CH:30](Br)[CH3:31])[CH3:27].[C:34]1([CH3:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:26]([O:28][C:29]([CH:30]1[CH2:31][N:8]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][N:11]1[CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH3:27]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccccc1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
A solution of N,N-dibenzylethylenediamine (980 μL, 4.10 mmol) and triethylamine (1.03 mL, 7.38 mmol) in toluene (15 mL) was added dropwise to a solution of 2-bromopropionic acid ethyl ester (601 μL, 4.14 mmol) in toluene (15 mL). The reaction mixture was stirred at 80° C. for 72 h. The reaction mixture was filtered through a pad of celite and solvent evaporated under reduced pressure to afford 1,4-dibenzylpiperazine-2-carboxylic acid ethyl ester (1.33 g, 3.93 mmol, 96%) as a yellow oil.
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1>C(OCC)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:3])=[O:14])[CH:11]=2)[CH:6]=[CH:5]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: CCOCC
Product: COC(=O)c1ccc2cc[nH]c2c1

Procedure:
An ethereal solution of diazomethane (620 mL) was added slowly to a cooled, (−15° C.) stirred suspension of 6-indole carboxylic acid (45 g, 0.27 mol.) in diethyl ether (250 mL). Upon addition, the reaction mixture was stirred for a further 1 h at −15° C., after which the reaction was quenched by the slow addition of acetic acid (50 mL). The resultant mixture was then concentrated under reduced pressure, and the residue purified using flash chromatography on silica (60-120), using MDC as eluant.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].[CH3:12][OH:13]>>[OH:11][NH:10][C:1](=[NH:8])[C:2]1[CH:7]=[CH:6][C:5]([CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#Cc1ccccc1
Reactant: NO
Agent: Cl
Product: N=C(NO)c1ccc(CO)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of the benzonitrile intermediate in methanol was added hydroxylamine hydrochloride. After heating to 50° C. with stirring for 16 h, the reaction mixture was cooled to RT and concentrated to afford the corresponding N-hydroxy-4-(hydroxymethyl)benz-imidamide derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH:21]=[CH:22]N(C)C)=[CH:16][CH:15]=3.Cl.[CH:33]1([NH:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH:33]1([N:39]2[C:20]([C:17]3[CH:18]=[C:19]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:27])[C:12]3[N:28]([CH3:31])[C:29](=[O:30])[C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:10][C:11]4=3)=[CH:21][CH:22]=[N:40]2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: NNC1CCCCC1
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: Cl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccnn4C4CCCCC4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 37 above, with the compound from preparation 1.10, 3-(2,4-dichlorophenyl)-6-[3-(dimethylamino)prop-2-enoyl]-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and cyclohexylhydrazine hydrochloride.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:5][CH:4]([S:6]([O-])(=[O:8])=[O:7])[CH2:3]1.[K+].S(Cl)([Cl:14])=O>CN(C=O)C>[F:1][C:2]1([F:10])[CH2:5][CH:4]([S:6]([Cl:14])(=[O:8])=[O:7])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])C1CC(F)(F)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)C1CC(F)(F)C1
Temperature: 60 °C
Yield: 100.2 %

Procedure:
To a suspension of potassium 3,3-difluorocyclobutane-1-sulfonate (0.250 g, 1.189 mmol) in thionyl chloride (2.60 mL, 35.7 mmol) was added DMF (3 drops). The reaction was heated to about 60° C. for about 21 h. The solvent was removed under reduced pressure and the residue was used in the next reaction without further workup or purification to afford crude 3,3-difluorocyclobutane-1-sulfonyl chloride (0.227 g, 100%) as product. 1H NMR (400 MHz, CDCl3) δ 4.33-4.17 (m, 1H), 3.28 (dd, J=11.1, 7.6 Hz, 2H), 3.21-3.05 (m, 2H).
Reaction SMILES: O.[OH-].[Li+].[OH:4][C@H:5]([CH3:35])[C@H:6]([O:8][C:9]1[CH:10]=[C:11]([O:24][C:25]2[N:26]=[CH:27][C:28]([C:31]([O:33]C)=[O:32])=[N:29][CH:30]=2)[CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:14]=1)[CH3:7].O[C@@H](C)[C@@H](OC1C=C(OC2N=CC(C(OC)=O)=NC=2)C=C(C(NC2C=CN(C)N=2)=O)C=1)C>O.C1COCC1>[OH:4][C@@H:5]([CH3:35])[C@@H:6]([O:8][C:9]1[CH:10]=[C:11]([O:24][C:25]2[N:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[N:29][CH:30]=2)[CH:12]=[C:13]([C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])[CH:14]=1)[CH3:7]
Reactant: COC(=O)c1cnc(Oc2cc(O[C@H](C)[C@@H](C)O)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: COC(=O)c1cnc(Oc2cc(O[C@@H](C)[C@H](C)O)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Lithium hydroxide monohydrate (38 mg, 0.88 mmol) in water (3 mL) was added to methyl 5-[(3-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate and methyl 5-[(3-{[(1S,2S)-2-hydroxy-1-methylpropyl]oxy}-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylate (1:1) (0.26 g, 0.59 mmol) in THF (6 mL) and the mixture stirred at RT for 72 hours. The THF was removed in vacuo and the aqueous residue adjusted to pH3 with citric acid, then extracted into ethyl acetate, washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound as a white solid (0.16 g).
Reaction SMILES: [CH3:1][Mg]Br.[CH2:4]([N:7]1[C:11]2=[C:12]([CH:16]=[N:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH3:25])=[C:8]1[CH3:26])[CH:5]=[CH2:6].[Cl-:27].[NH4+]>C(OCC)C>[ClH:27].[CH2:4]([N:7]1[C:11]2=[C:12]([CH:16]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH3:1])[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([CH3:25])=[C:8]1[CH3:26])[CH:5]=[CH2:6]
Reactant: C=CCn1c(C)c(C)c2ccnc(C=Nc3ccc(F)cc3)c21
Reactant: C[Mg]Br
Reactant: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCn1c(C)c(C)c2ccnc(C(C)Nc3ccc(F)cc3)c21
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylmagnesium bromide (3.0M in ethyl ether solution, 37 μl, 1.12 mmol) was added at 0° C. to a solution of N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethylene)-4-fluorophenylamine (30 mg, 0.112 mmol) prepared in Step 1 in anhydrous ethyl ether (5 ml). The reaction mixture was stirred for 2 hours at room temperature and then a saturated ammonium chloride solution (5 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (15 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting yellow oil was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered. The resulting solid was dried under reduced pressure to give 1.4 mg of the titled compound as a white solid.
Reaction SMILES: [OH:1]O.[OH-].[Na+].C[C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=O.O>CO.S(=O)(=O)(O)O>[CH3:14][CH:7]1[CH2:6][CH2:11][CH2:10][C:9](=[O:1])[C:8]1([CH3:13])[CH3:12]
Reactant: CC1=C(C=O)C(C)(C)CCC1
Reactant: OO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CCCC(=O)C1(C)C
Reaction time: 0.25 h

Procedure:
110 ml of a solution of 30 % H2O2 followed by 28 ml of a 6N aqueous solution of NaOH were added dropwise, while stirring and within 45 minutes and 15 minutes, respectively, to a cooled solution (0°-5°) of 40 g of β-cyclocitral (0.26 mole) in 300 ml of methanol which had been acidified beforehand with 40 drops of concentrated sulphuric acid. The reaction mixture was then kept at room temperature for 3 days, while stirring. After having added water thereto, the said mixture was extracted three times with ether and the combined organic extracts were subjected to the usual treatments of washing (water), drying (MgSO4) and concentration. There were obtained 21.5 g of trimethyl-cyclohexanone by fractional distillation; b.p. 66°-69°/12 Torr (66 %).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1>ClCCCl>[Cl:1][CH2:2][C:3]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][O:9][C:8]1[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=1[OH:6])=[O:4]
Reactant: Oc1ccccc1OCC1NCCS1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: O=C(CCl)N1CCSC1COc1ccccc1O
Temperature: -30 °C

Procedure:
Chloroacetylchloride (2.5 ml) is added to a stirred solution of 2-[(o-hydroxyphenoxy)methyl]thiazolidine (6 g) in 1,2-dichloroethane (80 ml) and triethilamine (4.3 ml) cooled at -30° C. After the usual work-up 3-α-chloroacetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (5.7 g, from Et2O, m.p. 89°-91° C.) is obtained. A stirred solution of the latter compound in 1,2-dichloroethane (50 ml) is heated with solid potassium thioacetate (4 g). After 2 hours, the mixture is washed with water to give, after the usual work-up, 3-acetylthio-acetyl-2-[(o-hydroxyphenoxy)methyl]thiazolidine (6.4 g, from EtOH) m.p. 97°-99° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:13](=[O:15])[CH3:14])([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C

Procedure:
The reaction of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol with acetic anhydride takes place at about -70° to +70° C. in a solvent such as dichloromethane to produce the N-(1,1-dimethylethyl)-N-(3,3,3-trichloro-2-hydroxypropyl)acetamide of this invention.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=C(C)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C[CH2:26][O:27][C:28]([CH3:30])=[O:29]>S(=O)(=O)(O)O>[CH3:26][O:27][C:28](=[O:29])[C:30]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 2-chloro-4-methyl-5-nitropyridine (Aldrich Chemical Co.) (5.0 g, 29.0 mmol) in concentrated sulfuric acid (60 mL) with stirring at 0° C., was added a solution of sodium dichromate dihydrate (14.3 g, 1.65 eq) in concentrated sulfuric acid (100 mL) at a rate which kept the internal temperature less than 10° C. After addition was complete, the reaction mixture was stirred from 0° C. to room temperature over 6 hours. By TLC, the reaction was not complete, so additional sodium dichromate dihydrate (8.4 g, 1 eq) was added directly to the solution at 0° C. The resulting solution was stirred from 0° C. to room temperature overnight. The reaction was complete by TLC the next morning, and it was poured into a mixture of ice (1 L) and EtOAc (900 mL). The resulting mixture was stirred for about 10 minutes and then the layers were separated. The organic layer was washed with brine (2×600 mL), and the EtOAc layer was dried over magnesium sulfate and filtered. With stirring at room temperature, trimethylsilyl diazomethathane (2.0M in hexanes, 15 mL) was added to the EtOAc filtrate. The resulting mixture was stirred at room temperature for 30 min. By TLC, there was no acid remaining, and then MeOH (150 mL) was added and the solution stirred for 30 minutes. The solution was concentrated and then EtOAc (700 mL) was added to the residue which was dried over magnesium sulfate, filtered, concentrated and pumped to give the title compound (1A) as an off-white powder (5.79 g, M+=216, M.P.=60.5–64.1° C.).