Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:17][C:16]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:11](=[O:25])[C:10]=2[C:9]=1[CH3:26])=O)(C)(C)C.FC(F)(F)C(O)=O.C(OC(OCC)OCC)C>>[CH2:23]([N:20]([CH2:21][CH3:22])[CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][CH2:15][C:16]2[NH:17][C:8]([CH:6]=[O:5])=[C:9]([CH3:26])[C:10]=2[C:11]1=[O:25])[CH3:24]
Reactant: CCN(CC)CCN1CCCc2[nH]c(C(=O)OC(C)(C)C)c(C)c2C1=O
Solvent: CCOC(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCN1CCCc2[nH]c(C=O)c(C)c2C1=O
Temperature: 40 °C
Yield: 81.6 %

Procedure:
5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 1i (0.413 g, 1.14 mmol) was dissolved in trifluoroacetic acid (1.5 ml, 20 mmol) under stirring, heated to 40° C. for 5 minutes in an oil bath under an argon atmosphere, and cooled down to −5° C. in an ice-salt bath under stirring, and added with triethoxy methane (0.34 ml, 1.7 mmol) and stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred for another about 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with 3 ml of ice water and 10 ml of dichloromethane, adjusted to pH 11 with aqueous sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (10 ml×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain yellow oil. The residue was purified by silica gel column chromatography to obtain the title compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 1j (0.271 g, yield 55%) as a light brown oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:28]=1[CH2:29]Br>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:29][C:28]2[C:31]([C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=[CH:34][C:27]=2[F:26])[N:18]=1)=[O:15]
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1Cl
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-chloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 45)(22 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (26 mg, 0.1 mmol, Aldrich) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=398, tRET=2.96 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]([NH:16][C@:17]2([C:22]([OH:24])=O)[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:15])[C:11]2=[N:25][NH:26][CH:27]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:40]1([S:43]([NH2:46])(=[O:45])=[O:44])[CH2:42][CH2:41]1.C1CCN2C(=NCCC2)CC1>ClCCCl>[CH:40]1([S:43]([NH:46][C:22]([C@@:17]2([NH:16][C:14]([CH:12]3[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]4=[CH:27][NH:26][N:25]=[C:11]34)=[O:15])[CH2:19][C@H:18]2[CH:20]=[CH2:21])=[O:24])(=[O:45])=[O:44])[CH2:42][CH2:41]1
Reactant: NS(=O)(=O)C1CC1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: C1CCC2=NCCCN2CC1
Product: C=C[C@@H]1C[C@]1(NC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of acid 8b (47.0 mg, 0.125 mmol) and CDI (22.3 mg, 0.150 mmol) in dry DCE (1.0 mL) was stirred at rt for 8 h. The cyclopropyl sulfonamide 9b (18.2 mg, 0.150 mmol) and DBU (22.8 mg, 0.150 mmol) were sequentially added and the mixture stirred at rt for 48 h. The solvent was evaporated and the residue diluted with EtOAc (2 mL). The mixture was washed sequentially with 0.5 M HCl (2×), deionized H2O and brine. The EtOAc solution was dried over MgSO4, filtered through a Celite plug capped with a layer of MgSO4 and concentrated. The crude product was purified via a SiO2 column (CH2Cl2, 25% EtOAc/hexanes then 50% EtOAc/hexanes) to give compound 104 as an ivory solid; 3:2 mixture of diastereomers, 27 mg, 45% (3:2 mixture of diastereomers), MS m/z 478.1 (APCI−, M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:18][C:19]1[N:20]=[C:21]([NH2:24])[S:22][CH:23]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:10]=1)[C:5]([NH:24][C:21]1[S:22][CH:23]=[C:19]([CH3:18])[N:20]=1)=[O:7]
Reactant: O=C(O)c1cc(F)cc(Oc2cncnc2)c1
Reactant: Cc1csc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cc(F)cc(Oc3cncnc3)c2)n1
Yield: 50.8 %

Procedure:
Compound 5 (1.0 g, 4.3 mmol, 1.0 eq), 4-methylthiazol-2-amine (585 mg, 5.12 mmol, 1.20 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (3.4 g, 8.9 mmol, 2.1 eq), and DIEA (1.56 mL, 8.94 mmol, 2.10 eq) were dissolved in CH2Cl2 (21 mL) and DMF (4.2 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 721 mg (51%) of the title compound as a tan solid: 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (s, 2H), 7.74-7.70 (m, 1H), 7.62 (t, J=1.6 Hz, 1H), 7.43 (dt, J=9.6, 2.3 Hz, 1H), 6.83 (d, J=1.0 Hz, 1H), 2.28 (s, 3H); [M+1]+: 331.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[O:31]C[O:29][C:5]=2[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:16]/[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=1.B(Cl)(Cl)Cl>ClCCl>[OH:29][C:5]1[CH:6]=[C:7]([CH2:9][C@@H:10]2[CH2:15][O:14][C:12](=[O:13])/[C:11]/2=[CH:16]/[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[OH:31]
Reactant: COc1cc(/C=C2/C(=O)OC[C@H]2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C[C@@H]2COC(=O)/C2=C/c2cc(OC)c(OC)c(OC)c2)cc(O)c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
In 10 ml of dichloromethane, 0.84 g (1.96 mmol) of (S)-(E)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]-2-(3,4,5-trimethoxybenzylidene)butanolide was dissolved. The solution was added with 4 ml of a 1.0M dichloromethane solution of boron trichloride (4 mmol), followed by stirring at 0° C. for 30 minutes. The solvent was distilled off under reduced pressure. After the residue was dissolved in a mixture consisting of 20 ml of methanol and 6 ml of 2N-HCl, the solution was stirred at 0° C. for 2 hours. The reaction mixture was extracted with ethyl acetate (50 ml×1, 20 ml×2). The organic layers were combined and washed successively with water and saturated NaHCO3, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 0.79 g of the title compound was obtained as pale yellow oil (yield: 97%).
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:19]=O>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: [O-][n+]1ccccc1C=Cc1ccc(Cl)c(Cl)c1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and 3,4-dichloro-benzaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=265 (M+).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[Br:45][C:46]1[CH:47]=[CH:48][C:49]([F:56])=[C:50]2[C:55]=1[CH2:54][NH:53][CH2:52][CH2:51]2>C(Cl)Cl.O>[Br:45][C:46]1[CH:47]=[CH:48][C:49]([F:56])=[C:50]2[C:55]=1[CH2:54][N:53]([C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:12])[CH2:52][CH2:51]2
Reactant: Fc1ccc(Br)c2c1CCNC2
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCc2c(F)ccc(Br)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (389 mg, 2.4 mmol, 1.2 eq.) in DCM (10 mL), DIPEA (1.37 ml, 8 mmol, 4.0 eq.) and TBTU (771 mg, 2.4 mmol, 1.2 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then 8-bromo-5-fluoro-1,2,3,4-tetrahydro-isoquinoline hydrochloride (533 mg, 2.0 mmol, 1.0 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was poured in water (50 mL). The mixture was extracted with DCM (2×30 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[C:5]2[NH:6][C:7](=[O:20])[C:8]3[C:13]([CH3:14])=[N:12][C:11]4[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=4[C:9]=3[N:4]2[N:3]=1.Cl[CH2:23][CH2:24][NH2:25].CN(CCCCl)C>>[NH2:25][CH2:24][CH2:23][N:6]1[C:7](=[O:20])[C:8]2[C:13]([CH3:14])=[N:12][C:11]3[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:10]=3[C:9]=2[N:4]2[N:3]=[C:2]([CH3:1])[CH:21]=[C:5]12
Reactant: CCn1ncc2c1nc(C)c1c(=O)[nH]c3cc(C)nn3c12
Reactant: NCCCl
Agent: CN(C)CCCCl
Product: CCn1ncc2c1nc(C)c1c(=O)n(CCN)c3cc(C)nn3c12

Procedure:
By substituting the 2,6-dimethyl-8-ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one obtained in Example 16 in the procedure of Example 4 and substituting 2-chloroethylamine for the dimethylaminopropyl chloride, 4-(2-aminoethyl)-2,6-dimethyl-8-ethyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C@H:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
To a mixture of 1-benzyl-3-(4-chloro-phenyl)-piperidin-4-one (15.2 g, 38.5 mmol) and piperazine (6.78 g, 77.1 mmol) in ethanol (6 mL) was added tetraisopropyl-orthotitanate (22.8 mL, 77.1 mmol) at room temperature. After stirring at room temperature for 3 days the reaction mixture was diluted with ethanol (250 mL) and sodium cyanoborohydride (5.10 g, 77.1 mmol) was added. The reaction mixture was stirred at room temperature for 24 h and was diluted with water (30 mL). The inorganic precipitate was filtered off and washed with ethanol and dichloromethane. The solvent was evaporated and the residue was taken up in ethylenglycol (100 mL) and sodium hydroxide (3.08 g, 77.1 mmol) was added. The reaction mixture was stirred at 130° C. for 15 min. After cooling water (200 mL) was added and the mixture was extracted four times with 200 mL tert.-butyl methyl ether. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with methylene chloride/methanol/triethyl amine 98:1:1 gave rac-cis-1-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine (9.54 g, 67%) as a yellow oil, MS: m/e=336.3 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)[O:5][N:4]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[CH3:15][C:14]([C:12]1[CH:13]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:7]=2)[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=1[OH:18])([CH3:17])[CH3:16]
Reactant: C1CCNC1
Reactant: CC(C)(C)c1cc(-c2nc(CCl)no2)cc(C(C)(C)C)c1O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-c2nc(CN3CCCC3)no2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.5 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.4 g (0.006 mole) of pyrrolidine in DMF (10 ml) is stirred at room temperature for three hours. The mixture is poured into ice water (50 ml) and extracted with ethyl acetate (3×25 ml). The organic phase is washed with water (3×40 ml), dried (anhydrous magnesium sulfate), and evaporated, leaving an oil. Purification by flash chromatography (silica gel, ethyl acetate/hexane elution) yields 0.4 g (73%) of analytically pure 2,6-bis(1,1-dimethylethyl)-4-[3-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol-5-yl]phenol, mp 100°-102° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:7]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]2[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=2[N:8]=1)[C:4](O)=[O:5].Cl.Cl.[CH2:26]([O:33][C:34](=[O:46])[NH:35][C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1)=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([O:33][C:34](=[O:46])/[N:35]=[C:36](/[NH2:37])\[C:38]1[CH:39]=[CH:40][C:41]([CH2:44][NH:45][C:4](=[O:5])[CH:3]([O:2][CH3:1])[C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]3[CH:20]=[CH:21][CH:22]=[CH:23][C:9]=3[N:8]=2)=[CH:42][CH:43]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: COC(C(=O)O)c1nc2ccccc2n1COCC[Si](C)(C)C
Agent: Cl
Product: COC(C(=O)NCc1ccc(/C(N)=N\C(=O)OCc2ccccc2)cc1)c1nc2ccccc2n1COCC[Si](C)(C)C

Procedure:
According to general procedure C, (RS)-methoxy-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-acetic acid was reacted with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-[1-amino-1-[4-({2-methoxy-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-acetylamino}-methyl)-phenyl]-meth-(E)-ylidene]-carbamic acid benzyl ester. Light yellow solid. MS 602.3 ([M+H]+)
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S]>>[C:1]1([S:7][S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Agent: [S]
Product: c1ccc(SSc2ccccc2)cc1

Procedure:
To the same reactor, 220 g of thiophenol, 16 g of sulphur and 4 g of Amberlyst A 21 resin are added. The mixture is kept at ambient temperature while stirring. At the end of the evolution of hydrogen sulphide, the liquid is recovered. The analysis of which shows that it is wholly composed of diphenyl disulphide and excess thiophenol. The yield of diphenyl disulphide is 99% in relation to the sulphur added.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27](O)=[O:28])[N:11]=1.CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)=[O:28])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CC(=O)O)c2cc(Nc3ccccc3)ccc12
Reactant: CN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C)c1Nc1nn(CC(=O)N2CCN(C)CC2)c2cc(Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.26 mmol) of 2-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-indazol-1-yl)acetic acid 69 (Example 34) in DCM (10 mL) at room temperature was treated with Et3N (43 μL, 1.2 eq) followed with Bop-Cl (73 mg, 1.1 eq) and 1-methylpiperazine (35 μL, 1.2 eq). The mixture was stirred at room temperature for 3 hours before it was quenched with water (5 mL). The organic layer was separated and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluens: DCM:MeOH:NH4OH, 20:1:0.2) to give the title compound 70. 1H-NMR (CDCl3) δ 2.28 (s, 6H), 2.32 (s, 3H), 2.35-2.45 (m, 4H), 3.59-3.69 (m, 4H), 4.98 (s, 2H), 5.91 (s, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.08-7.16 (m, 3H), 7.19 (s, 1H), 7.32 (t, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=7.7 Hz, 2H). Mass Spectrum (ESI) m/e=471 (M+1).
Reaction SMILES: [C:1]1(=O)[C:12]2[C:4](=[CH:5][C:6]3[CH2:7][CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:3][CH2:2]1.Cl.[H][H]>[Pd].C(O)C>[CH2:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[CH2:1][CH2:2]1
Reactant: O=C1CCc2cc3c(cc21)CCC3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1c2c(cc3c1CCC3)CCC2
Yield: 73.8 %

Procedure:
A mixture of 3,5,6,7-tetrahydro-2H-s-indacen-1-one (90 grams), ethanol (1 L), 10% palladium on carbon (1-2 grams) and concentrated hydrochloric acid (50 mL) was hydrogenated on a Parr shaker at room temperature until hydrogen uptake ceased. The mixture was filtered through a Celite pad. The pad was washed with 1 L diethyl ether. The filtrate was diluted with water and the organic phase was separated. The aqueous phase was extracted with 1 L of ether, and the combined ether extracts were washed with water, saturated sodium bicarbonate solution and brine. The ether extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting pale yellow solid was recrystallized from methanol to afford 61 grams of the title compound as colorless crystals, m.p. 56.6-58.5° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][CH2:9][CH:10](O)[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH:14](O)[CH2:15][F:16].CS(Cl)(=O)=O.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.C(O)C>[CH2:31]([N:38]1[CH:10]([CH2:9][F:8])[CH2:11][N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:14]1[CH2:15][F:16])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OC(CF)CN(Cc1ccccc1)CC(O)CF
Reactant: NCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: FCC1CN(Cc2ccccc2)CC(CF)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
28.89 g (0.286 mole) of triethylamine were added to a solution of 33.67 g (0.13 mole) of N,N-bis(3-fluoro-2-hydroxypropyl)benzylamine [prepared as described in step (a) above] in 300 ml of tetrahydrofuran. 32.76 g (0.286 mole) of methanesulfonyl chloride were then added dropwise to the mixture, whilst ice-cooling. After the mixture had been stirred at room temperature for 6 hours, 39.40 g (0.39 mole) of triethylamine, 20.87 g (0.195 mole) of benzylamine and 300 ml of ethanol were added to it, and it was then heated under reflux for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and 300 ml of water containing 30 g of sodium hydroxide were added to the residue. The aqueous mixture thus obtained was extracted with ethyl acetate and the organic extracts were washed with water, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel using a 20:1 by volume mixture of toluene and ethyl acetate as the eluent, to afford 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine, including 6.29 g of isomer A and 6.60 g of isomer B, as colorless crystals.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=1[F:16].[Br:19][C:20]1[S:21][C:22]([C:26](O)=[O:27])=[C:23]([CH3:25])[N:24]=1>>[Br:19][C:20]1[S:21][C:22]([C:26]([NH:18][CH2:17][C:12]2[CH:13]=[CH:14][C:15]([F:16])=[C:10]([F:9])[CH:11]=2)=[O:27])=[C:23]([CH3:25])[N:24]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(Br)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(Br)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 61 %

Procedure:
Following the procedure as described in Preparation 8, making variations as required to replace benzyl amine with (3,4-difluorophenyl)methanamine to react with 2-bromo-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 61% yield: 1H NMR (300 MHz, CDCl3) δ 7.16-7.01 (m, 3H), 6.08-5.94 (m, 1H), 4.52 (d, J=5.9 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 347.2 (M+1), 349.2 (M+3).
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1>C1COCC1.O>[Br:2][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=2)[NH:10][CH:9]=1
Reactant: CS(=O)(=O)NCc1ccc2[nH]cc(CCO)c2c1
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)NCc1ccc2[nH]cc(CCBr)c2c1
Reaction time: 3.5 h

Procedure:
Phosphorus tribromide (0.03 ml) was added dropwise to a solution of N-[[3-(2-hydroxyethyl)-1H-indol-5-yl]methyl]methanesulphonamide (0.18 g) in dry THF (20 ml) stirred in an ice bath. There was an immediate reddish colour produced. The solution was stirred for 2 h and then at room temperature for a further 3.5 h, then again chilled in ice, diluted with water (40 ml) and extracted with ether (2×50 ml, 3×25 ml) combined extracts were washed with brine (3×20 ml) and dried (Na2SO4). Removal of the solvent by rotary evaporation at 35°-40° afforded the title compound as a viscous pink oil (0.22 g).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:37][C:38](=[O:48])[N:39]([CH3:47])[CH:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:30]([O:37][C:38](=[O:48])[N:39]([CH:40]1[CH2:45][CH2:44][C:43](=[CH:2][O:3][CH3:4])[CH2:42][CH2:41]1)[CH3:47])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)OCc1ccccc1)C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=C1CCC(N(C)C(=O)OCc2ccccc2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 654.8 %

Procedure:
A suspension of 749.88 g (2187.5 mmol) (methoxymethyl)triphenylphosphonium chloride in 2.5 l THF was cooled to −10° C. and deprotonated with 245.5 g (2187.5 mmol) potassium t-butoxide. The dark red solution was stirred at 0-5° C. for 0.5 h, cooled to −20° C. and 457.32 g (261.33 mmol) of Methyl-(4-oxo-cyclohexyl)-carbamic acid benzyl ester in 1.25 l THF were added over a period of 1.25 h. After 1.3 h at RT, the reaction was treated with 1.75 l aqueous 1M NaHCO3 and stirred for 45 min. The phases were separated, the aqueous phase was extracted with TBME (700 ml), the organic phase was dried (Na2SO4), filtered and evaporated. The residue was suspended in hexane (5 l), cooled (0° C.), filtered and evaporated to give 495.2 g (98%) of (4-Methoxymethylene-cyclohexyl)-methyl-carbamic acid benzyl ester, MS: 289 (M).