Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:12]2[N:13]=[CH:14]C=CC=2N=N1.[CH:25]([N:28]([CH:31]([CH3:33])C)[CH2:29][CH3:30])(C)C.Cl.[N:35]1([CH:41]2[CH2:46][CH2:45][N:44]([C:47]3[CH:55]=[CH:54][C:50]([C:51]([OH:53])=O)=[CH:49][CH:48]=3)[CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>CN(C)C=O>[CH3:12][N:13]([CH:14]1[CH2:30][CH2:29][N:28]([CH3:25])[CH2:31][CH2:33]1)[C:51](=[O:53])[C:50]1[CH:49]=[CH:48][C:47]([N:44]2[CH2:43][CH2:42][CH:41]([N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)[CH2:46][CH2:45]2)=[CH:55][CH:54]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(N2CCC(N3CCCCC3)CC2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)c2ccc(N3CCC(N4CCCCC4)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 43.9 %

Procedure:
At room temperature, 1-methyl(4-methylamino)piperidine (0.056 ml, 0.38 mmols), O-(7-azabenzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmols) and diisopropylethylamine (0.17 ml, 0.96 mmols) were added to a dimethylformamide solution (1.0 ml) of 4-[(4-piperidin-1-yl)piperidin-1-yl]benzoic acid hydrochloride (103 mg, 0.32 mmols) obtained in Reference Example 1, and stirred in a nitrogen atmosphere at room temperature for 14 hours. The reaction solution was extracted with ethyl acetate, the organic layer was washed with water, saturated sodium bicarbonate solution and saturated saline solution in the order, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified through preparative thin-layer chromatography (chloroform/methanol/aqueous ammonia=10/1/0.1) to obtain the entitled compound (56 mg, 44%).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]([Cl:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C.O>[Cl:15][C:2]([Cl:1])=[CH:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([Cl:14])[C:9]([O:13][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:10]([Cl:12])[CH:11]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 18 h
Yield: 102.4 %

Procedure:
A mixture of 0.5 gram (0.0017 mole) of 4-(3,3-dichloroprop-2-enyloxy)-2,6-dichlorophenol (known compound), 0.26 gram (0.0019 mole) of potassium carbonate and 0.26 gram (0.0017 mole) of tert-butyl chloroacetate in 0.12 mL of DMF was heated to 70° C. where it stirred for about 18 hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 30 mL of water then extracted with three 30 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a yellow oil. The crude oil was purified with column chromatography on silica gel using a mixture of hexanes and ethyl acetate (93:7) as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.7 gram of the subject compound.
Reaction SMILES: [Na].Cl[CH:3]=[C:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][CH2:6][C:5]1=O.[Li+].[OH-].C([O:17][C:18](=[O:21])[CH2:19][SH:20])C>CCO.C1COCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][CH2:6][C:5]2=[C:19]([C:18]([OH:21])=[O:17])[S:20][CH:3]=[C:4]2[CH2:9]1
Reactant: CCOC(=O)CS
Reactant: CC1(C)CCC(=O)C(=CCl)C1
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCc2c(csc2C(=O)O)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a part (300 mL) of a freshly prepared solution of sodium (21 g, 875 mmol) in EtOH (500 mL), mercaptoacetic acid ethyl ester (50 mL) is added. The resulting solution is added over a period of 10 min to a solution of 2-chloromethylene-4,4-dimethyl-cyclohexanone (50 g, 290 mmol) in THF (170 mL). The mixture becomes warm (50° C.). Upon complete addition, the remaining part of the freshly prepared solution of sodium in EtOH (200 mL) is added to the reaction mixture. The mixture is stirred at rt for 15 min before 1 N aq. LiOH solution (300 mL) is added. The solution is refluxed for 3 h, then stirred at rt for 16 h. The THF and EtOH are removed under reduced pressure and the remaining dark solution is extracted with heptane/EA 3:1 (2×200 mL). The aqueous phase is acidified by adding citric acid (30 g) and 2 N aq. HCl (200 mL) and then extracted three times with EA. The combined organic extracts are washed three times with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The resulting dark brown oil is dissolved in acetonitrile at 60° C. and crystallised at 5° C. The crystals are collected, washed with acetonitrile and dried to give 5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid (31 g) as a slightly grey powder; LC-MS: tR=0.95 min, [M+1+CH3CN]+=252.18; 1H NMR (CDCl3): δ 7.15 (s, 1 H), 3.05 (t, J=7.0 Hz, 2H), 2.47 (s, 2H), 1.58 (t, J=7.0 Hz, 2H), 0.97 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[CH2:2]([C:18]1[O:19][CH:20]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCc1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Bromotetradecane (2.05 g, 8.17 mmol) in THF (4 mL) was added dropwise and the resulting solution was warmed to room temperature and stirred overnight. The reaction was quenched with a saturated solution of NH4Cl (5 mL). The organic layer was removed and the aqueous layer extracted with ether (3×5 mL). The combined organic layers were washed with a saturated solution of NaHCO3 (1×5 mL), brine (1×5 mL), dried over MgSO4, filtered and concentrated. The crude residue was passed through a small silica gel plug and recrystallized in methanol to afford the 2-(tetradecyl)furan, compound (20) (1.50 g, 77% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:14][Br:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>ClCCl>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH:2]([CH2:14][Br:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C1=COCCC1
Reactant: O=C(CC(O)CBr)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CC(CBr)OC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
The product of step 2 (845 mg, 3.09 mmoles) was dissolved in dichloromethane (10 mL), and dihydropyran (300 μL, 277 mg, 3.29 mmole) and p-toluenesulfonic acid monohydrate (3 crystals) were added. The solution was stirred at room temperature for 1.5 h. Diethyl ether (40 mL) was then added, and the solution was washed with saturated sodium bicarbonate (2×40 mL), dried over anhydrous sodium sulfate, and evaporated. Purification by column chromatography using ethyl acetate-hexanes (3:7) gave benzyl 3-[2-tetrahydropyranyloxy]-4-bromobutanoate (1.07 g, 97%) as a 1:1 mixture of diastereisomers. IR (neat): 3033, 1737 cm−1. Mass spectrum (CI, m/z): 357, 3539 (M+1, m+3). Calcd. for C16H21BrO4: C 53.75; H 5.88. Found: C 53.65; H 5.60.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[C:30]=[O:31]>C(Cl)Cl>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([NH:29][C:30]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:31])[CH:33]=1
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2cccnc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 30 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (40 mg, 0.095 mmol) and 3-isocyanatopyridine (Oakwood, 29.1 mg, 0.242 mmol) in CH2Cl2 (5 mL) was stirred at rt for 17 hrs. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid pyridin-3-ylamide (15.5 mg, 30%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[N:20]=[C:19]3[N:21]([CH2:24][C:25]4[CH:26]=[C:27]5[C:32](=[CH:33][CH:34]=4)[N:31]=[CH:30][CH:29]=[CH:28]5)[N:22]=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:12]=[N:11]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>CO.O>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([CH2:24][N:21]3[C:19]4=[N:20][C:15]([C:13]5[CH:12]=[N:11][N:10]([CH2:9][CH2:8][OH:7])[CH:14]=5)=[CH:16][CH:17]=[C:18]4[N:23]=[N:22]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: c1cnc2ccc(Cn3nnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nc43)cc2c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a solution of example 145 (0.190 g, 0.417 mmol) in methanol (2 ml) and water (2 ml), camphor sulphonic acid (0.968 g, 4.17 mmol) was added and stirred for 1 h. The reaction was poured into ice water and the pH was adjusted to ca 8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by recrystallisation from isopropanol to afford the title compound as a light yellow solid (0.059 g, 38%). M.P.: 179-178° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.49 (s, 1H), 8.38 (dd, J=8.3, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.82 (dd, J=8.7, 1.7 Hz, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.11 (s, 2H), 4.96 (t, J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.79 (dd, J=10.8, 5.4 Hz, 2H). MS (m/z):: 372.08 (M++1).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.C(N(CC)CC)C.Cl[SiH2:20][CH:21]=[C:22]([CH3:24])[CH3:23].Cl>C1(C)C=CC=CC=1>[CH3:23][C:22]([CH3:24])=[CH:21][SiH2:20][O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2
Reactant: CC(C)=C[SiH2]Cl
Reactant: OC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)=C[SiH2]OC1C2CC3CC(C2)CC1C3

Procedure:
2-Tricyclo[3.3.1.13,7]decanol (25 g), triethylamine (28 g) and toluene (250 g) were charged in a four-necked 500 ml flask, and then chlorodimethylvinylsilane (30 g) was dropwise added to the mixture at 40° C. over one hour while well stirring. The mixture was stirred at 40° C. for 7 hours with monitoring the progress of the reaction by gas chromatography. After the completion of the reaction, a 4% hydrochloric acid (300 ml) was added to the reaction mixture, and then the mixture was separated. The organic layer was washed with water and concentrated by evaporating off toluene contained in the organic layer, and the residue was distilled under reduced pressure to obtain 2-dimethylvinylsiloxy-tricyclo[3.3.1.13,7]decane having the following structure (40 g):
Reaction SMILES: OC1C=C(N[C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18](O)[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)C=CC=1.Cl[C:25]1N=C(Cl)C(F)=CN=1.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([NH:40][C:9]1[N:14]=[C:13]([NH:15][CH2:16][C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:25]=2)[C:12]([F:23])=[CH:11][N:10]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCc1ccccc1
Product: Fc1cnc(NCc2ccccc2)nc1NCc1ccccc1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and benzylamine were reacted to yield N2,N4-bis(benzyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.69 (bs, 1H), 7.35-7.24 (m, 10H), 5.63 (bs, 1H), 5.27 (bs, 1H), 4.61 (d, 2H, J=6.0 Hz), 4.55 (d, 2H, J=6.0 Hz); 19F NMR (CDCl3): −48580; LCMS: ret. time: 23.73 min.; purity: 100%; MS (m/e): 309 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[NH:13][C:12]2=[O:28])=[CH:2]1>CCCCCC.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([CH2:10][CH:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:15]3[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=3[NH:13][C:12]2=[O:28])[CH2:2]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=N[C@@H]1Cc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1Nc2ccccc2C(c2ccccc2)=NC1CC1CNc2ccccc21

Procedure:
The procedure of Example 9 was followed in which 3(R)-[(1H-indol-3-yl)methyl]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one was reduced to give the tile compound. The analytical sample was obtained after silica gel chromatography using hexane-ethyl acetate.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]([NH2:7])=[O:6])[CH3:4].O=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](OCC)=[O:13]>>[CH3:4][C@H:3]1[N:2]2[C:12](=[O:13])[CH2:11][CH2:10][C@@:9]2([CH3:17])[NH:7][C:5]1=[O:6]
Reactant: CCOC(=O)CCC(C)=O
Reactant: CC(N)C(N)=O
Agent: Cl
Product: C[C@@H]1C(=O)N[C@]2(C)CCC(=O)N12

Procedure:
DL-Alaninamide hydrochloride (6.9 g), 0.055 mol) and ethyl 4-oxopentanoate (6.7 g, 0.043 mol) were reacted together according to the procedure of Example 2 to give the title compound, 1.65 g (22.8%), m.p. 184°-192°. NMR (DMSO-d6 : deltaH =8.80 (bs, 1H, NH); 3.90 (q, J=7.5 Hz, 1H, CHCH3) 3.00-2.00 (c.a., 4H, CH2CH2); 1.42 (s, 3H, C--CH3); 1.22 (d, J=7.5 Hz, 1H, CHCH3)
Reaction SMILES: C[CH:2]([B:7]([O:12][CH:13]([CH3:15])[CH3:14])OC(C)C)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18]#[C:19][Li].Cl.[B].[CH2:25]=C(C)C>C(OCC)C>[CH2:2]([B:7]([C:19]#[C:18][C:17]([CH3:22])([CH3:21])[CH3:16])[O:12][CH:13]([CH3:14])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:25]
Reactant: [Li]C#CC(C)(C)C
Reactant: CCCCC(C)B(OC(C)C)OC(C)C
Reactant: C=C(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCB(C#CC(C)(C)C)OC(C)C

Procedure:
n-Hexyl(3,3-dimethyl-1-butynyl)isopropoxyborane was prepared by adding 2-n-hexyl-diisopropoxyborane (8.35 g, 39 mmol) in ethyl ether (18 mL) to an ethyl ether solution of 3,3-dimethyl-1-butynyllithium (44 mmol in 44 mL of ethyl ether), following the method of Example 14, and quenched with HCl in ethyl ether (12.87 mL, 44 mmol). Yield: 7.2 g (79%), bp 80°-82° C. (0.1 mm Hg); n20D 1.4265, boron NMR (ethyl ether) δ+40.6 ppm(s); mass spectrum (chemical ionization, isobutene) m/e 237 (M+H, 7%); IR (thin film) 2186, 1327 cm-1. Anal. Calcd. for C15H29BO: C, 76.23; H, 12.38; B, 4.58. Found: C, 76.35; H, 12.02; B, 4.61.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>CC#N>[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:5][CH3:3])=[O:14]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1cccnc1Cl
Agent: CN
Solvent: CC#N
Product: CNC(=O)c1cccnc1Cl
Temperature: 23 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
Methanamine (0.425 mL, 3.41 mmol) and triethylamine (0.792 mL, 5.68 mmol) were dissolved in CH3CN (14.2 mL) at 23° C. 2-Chloronicotinoyl chloride (500 mg, 2.84 mmol) was added and the reaction mixture was stirred at 23° C. for 16 h. The solvent was removed by rotary evaporation and the residue was partitioned between EtOAc (20 mL) and sat. aq. NaHCO3 (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were dried over MgSO4 and concentrated. Trituration of the resulting solid with 5% EtOAc-hexane provided the desired product as a white powder (153.2 mg, 31%). 1H NMR (CD3OD) δ 8.43 (dd, 1H, J=5.09, 2.03 Hz), 7.88 (dd, 1H, J=7.63, 2.03 Hz), 7.45 (dd, 1H, J=7.38, 4.83 Hz), 2.91 (s, 3H); MS(ESI+) m/z 171.1 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:6]([CH3:7])[CH2:5][C:4](=O)[CH2:3]1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[C:4]1[CH2:3][C@@H:2]([CH3:1])[C@H:6]([CH3:7])[CH2:5]1)[CH3:16]
Reactant: CCOC(=O)CC#N
Reactant: C[C@@H]1CC(=O)C[C@H]1C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1C[C@@H](C)[C@H](C)C1
Yield: 93 %

Procedure:
Trans-3,4-dimethyl cyclopentanone (2.91 g, 25.94 mmol), ethyl cyanoacetate (2.93 g, 25.93 mmol), ammonium acetate (0.20 g, 2.60 mmol), and acetic acid (0.31 g, 5.17 mmol) were heated together in refluxing toluene under a Dean-Starck trap for 24 hours. After cooling and filtration through kieselguhr, evaporation gave the required product as an off-white solid (5.0 g, 93%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24](=[O:27])([O-:26])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:9]([OH:11])(=[O:10])[C:24]([OH:26])=[O:27].[CH3:1][N:2]([CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: ClCC=Cc1ccccc1
Reactant: CCOC(=O)N1CCC(NC)CC1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)N1CCC(N(C)C/C=C/c2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 14 parts of ethyl 4-(methylamino)-1-piperidinecarboxylate, 13 parts of (3-chloro-1-propenyl)benzene, 26.5 parts of sodium carbonate and 240 parts of 4-methyl-2-pentanone was stirred and refluxed over week-end using a water separator. The reaction mixture was cooled, water was added and the layers were separated. The organic phase was dried, filtered and evaporated. The residue was converted into the ethanedioate salt in 2-propanol and 2-propanone. The salt was filtered off and dried, yielding 23.4 parts of (E)-ethyl 4-[methyl(3-phenyl-2-propenyl)amino]-1-piperidinecarboxylate ethanedioate (1:1); mp. 160.2° C. (intermediate 3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1.C([Li])CCC.CON(C)[C:22](=[O:24])[CH3:23]>C1COCC1.[Cl-].[Na+].O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[C:4]([Cl:13])[CH:3]=1)(=[O:24])[CH3:23]
Reactant: CC(C)(C#N)c1ccc(Br)cc1Cl
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
To a stirred solution of 2-(4-bromo-2-chlorophenyl)-2-methylpropanenitrile (2.85 g, 11.0 mmol) in anhydrous THF (60 mL) at −78° C. is added n-butyllithium (2 M in c-hexane) (60.1 mL, 12.1 mmol). The reaction mixture is stirred at this temperature 10 min., then N-methoxy-N-methyl-acetamide (2.34 mL, 22.0 mmol) is added neat and the solution is stirred 10 min. at −78° C. and then warmed up to room temperature for another hour. Acidic brine (60 mL) is then slowly added and the solution is extracted with EtOAc (3×60 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (eluent: Hex/EtOAc 1:0 to 7:3) to provide the expected product 2-(4-acetyl-2-chlorophenyl)-2-methylpropanenitrile (1.57 g, 64%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.96 (1H, d, J=1.9 Hz), 7.81 (1H, dd, J=8.3, 1.9 Hz), 7.55 (1H, d, J=8.3 Hz), 2.56 (3H, s), 1.85 (6H, s).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][NH:12][C:11]=2[NH2:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:19][CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH2:26]C)=O>C(O)(=O)C>[C:1]1([S:7]([C:10]2[C:14]([S:15][CH3:16])=[N:13][N:12]3[C:20]([OH:19])=[CH:21][C:22]([CH2:23][O:25][CH3:26])=[N:17][C:11]=23)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)COC
Reactant: CSc1n[nH]c(N)c1S(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Product: COCc1cc(O)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Yield: 84.8 %

Procedure:
A solution of 2.69 g (10 mmol) 4-benzenesulphonyl-5-methylsulphanyl-2H-pyrazol-3-ylamine and 1.46 g (10 mmol) of ethyl 4-methoxy-acetoacetate in 10 ml of acetic acid was heated at reflux for 3 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was extracted three times with 80 ml of CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 25:1) yielded 3.1 g (85%) of 3-benzenesulphonyl-5-methoxymethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige powder, m.p. 175-155°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O-])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[F:28][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]([N:43]2[CH2:42][CH2:41][CH2:40][CH2:38]2)=[O:18])[CH:13]=4)[CH:25]=[CH:24][C:23]=1[O:26][CH3:27]
Reactant: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)[O-])ccc4c3c2)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCC5)ccc4c3c2)cc1F
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
8-Carbamoyl-6-(3-fluoro-4-methoxyphenyl)-9H-carbazole-2-carboxylic acid (16 mg, 0.042 mmol, Example 395), HATU (24.12 mg, 0.063 mmol) and DIPEA (0.022 mL, 0.127 mmol) were dissolved in DMF (1 mL) and stirred for 10 minutes. Pyrrolidine (9.2 mg, 0.13 mmol) was added and the mixture shaken over night. Purification by prep HPLC gave 9.4 mg 3-(3-fluoro-4-methoxyphenyl)-7-(pyrrolidine-1-carbonyl)-9H-carbazole-1-carboxamide. HPLC retention time 4.36 min. (Ascentis 4.6×50 mm 5 um C18, 2 ml/min, 0 to 100% B in 8 minutes, then 100% B for 1 minute. Solvent A: 5% CH3CN—95% H2O—10 mM NH4OAc; Solvent B: 95% CH3CN—5% H2O—10 mM NH4OAc). MS (ESI) m/e+=432 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].C(O[CH:9]=[CH:10][C:11](=O)[C:12](Cl)([F:14])[F:13])CCC.[CH2:17](O)C>>[F:13][CH:12]([F:14])[C:11]1[N:3]([CH3:17])[N:2]=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCCCOC=CC(=O)C(F)(F)Cl
Reactant: CCO
Solvent: O
Product: Cn1nccc1C(F)F
Reaction time: 0.17 h

Procedure:
Over a period of 10 minutes, hydrazine hydrate (80% pure, 0.52 g, 0.008 mol) was added dropwise to a solution of 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one (1.2 g, 0.005 mol) in ethanol (6 ml). The mixture was then stirred under reflux conditions for 5 h. The resulting yellow-brown suspension was concentrated on a rotary evaporator. The residue was taken up in ethyl acetate (20 ml) and water (20 ml). After separation of the phases, the aqueous phase was re-extracted with ethyl acetate (20 ml). The organic phases were combined, dried over MgSO4 and filtered, and volatile components were removed under reduced pressure. The light-red oily residue (0.35 g) consisted to about 65% of 3-difluorochloromethyl-NH-pyrazole and to 35% of ethyl pyrazole-3-carboxylate.