Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[C:17]([C:28]([NH2:30])=[O:29])[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5].[CH3:31][NH:32][CH3:33].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[CH3:31][N:32]([CH3:33])[CH2:2][CH2:3][S:4]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[C:21]3[C:16](=[C:17]([C:28]([NH2:30])=[O:29])[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5]
Reactant: CNC
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
To a solution of 3-{1-[(2-chloroethyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (26 mg, 0.063 mmol) in CH3CN (5 mL), dimethylamine (0.16 mL, 0.315 mmol), K2CO3 (35 mg, 0.252 mmol) and NaI (cat. 0.5 mg) were added. The reaction mixture was stirred at 80° C. for 16 hours. The solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting residue was purified by reverse phase HPLC (CH3CN/water, 0.1% TFA) to give title compound (14 mg, 48%).
Reaction SMILES: S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH:19]=O)=[N:11]1.[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH2:29])=[C:24]([NH2:30])[CH:23]=1>CN(C)C=O>[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]2[NH:29][C:19]([C:12]3[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10][N:11]=3)=[N:30][C:24]=2[CH:23]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=Cc1n[nH]c2ccccc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]c4ccccc34)[nH]c2cc1C
Temperature: 20 °C
Yield: 25.8 %

Procedure:
389 mg of sodium metabisulphite are added, at a temperature in the region of 20° C., to a solution of 300 mg of 1H-indazole-3-carboxaldehyde and 279 mg of 4,5-dimethyl-1,2-phenylenediamine in 3 ml of dimethylformamide. The reaction mixture is refluxed for 4 hours and then cooled to a temperature in the region of 20° C. and filtered through paper. The collected filtrate is concentrated under reduced pressure. The brown lacquer obtained (340 mg) is purified by preparative LC-MS. 138.8 mg of 5,6-dimethyl-2-(1H-indazol-3-yl)-1H-benzimidazole are thus obtained in the form of a beige-coloured powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:14][C:15](OC)=[O:16])[CH2:11][CH2:10][N:9]1[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[NH3:37]>>[CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:14][C:15](=[O:16])[NH2:37])[CH2:11][CH2:10][N:9]1[C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Solvent: CO
Product: NC(=O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
(2R)-2-Benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(methoxycarbonylmethyl)piperazine (0.2 g) was treated with 20% ammonia methanol solution (5 ml), and the resulting mixture was left overnight in a refrigerator. The reaction mixture was concentrated under reduced pressure and the residue was purified on a silica gel column (7 g) eluting with a mixture of dichloromethane and methanol (10:1) to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carbamoylmethyl)-piperazine. This compound was treated with 4N hydrogen chloride in ethyl acetate solution to give the corresponding hydrochloride (0.18 g) as a white powder.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[C:6]([CH:11]1[S:16][CH2:15][CH2:14][CH2:13][S:12]1)([O:8][CH2:9][CH3:10])=[O:7]>>[CH:5]1([CH2:4][C:11]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:12][CH2:13][CH2:14][CH2:15][S:16]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1SCCCS1
Reactant: BrCC1CC1
Product: CCOC(=O)C1(CC2CC2)SCCCS1

Procedure:
Preferably R3 is methyl, ethyl or isopropyl. Most preferably R3 is ethyl and the compound of Formula 5 is prepared by (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of a strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with bis(2-methoxyethyl)aminosulfur trifluoride.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=O)#[N:2].CC(C)([O-])C.[K+]>C1C=CC=CC=1>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[O:4][C:3]=2[C:1]#[N:2])=[CH:10][CH:11]=1
Reactant: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: Cc1ccc(-c2c(C#N)oc3ccccc23)cc1
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a mixture of 2-cyanomethoxy-4'-methylbenzophenone (18.6 g) and molecular sieves (18 g) in benzene (270 ml) was added potassium tert-butoxide (8.31 g) in one portion at ambient temperature. After stirring at the same temperature for one hour, the mixture was filtered off. The filtrate was washed with diluted hydrochloric acid, dried, and concentrated in vacuo. The residue was purified by flash column chromatography to yield 3-(4-methylphenyl)benzo[b]furan-2-carbonitrile (1.82 g) as white crystals.
Reaction SMILES: [N:1]([C:4]1([CH3:11])[CH:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-]C#N.[Na+]>CO.C(Cl)Cl.CO>[N:1]([C:4]1([CH3:11])[CH2:5][CH2:6][N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][CH2:8][CH:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: NCc1ccccc1
Reactant: CC1(N=[N+]=[N-])CC=CCC1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC1(N=[N+]=[N-])CCN(Cc2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of 6-azido-6-methylcyclohex-3-enol (3.9 g, 25 mmol) in MeOH/DCM (100 mL/20 mL) cooled to −78° C. was degassed by bubbling nitrogen through it for 5 min. Ozone was then bubbled through the reaction mixture until a greyish-blue colour persisted. Nitrogen was again bubbled through the cold reaction mixture until only a pale colour persisted. A solution of benzylamine (2.7 g, 25 mmol) dissolved in MeOH (5 mL) was added followed by NaCNBH3 (6.4 g, 101.5 mmol) in MeOH (10 mL). The mixture was allowed to warm to room temperature and stirred for 16 hr. The solvents were removed under reduced pressure and the residue partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was further extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine (40 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (1-10% 7 M NH3 in MeOH/DCM) gave 5-azido-1-benzyl-5-methylazepan-4-ol as a viscous yellow oil (4.8 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.34 (m, 5H), 3.69-3.62 (m, 2H), 3.51-3.47 (m, 2H), 2.96-2.89 (m, 1H), 2.69-2.62 (m, 3H), 2.19-2.11 (m, 1H), 1.99-1.85 (m, 1H), 1.78-1.68 (m, 1H), 1.61-1.57 (m, 1H), 1.43 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:24])[C:4]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:13]([CH2:21][CH2:22][CH3:23])[C:5]=2[O:6][C:7]=1[C:8]([O:10]CC)=[O:9].Cl>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[C:13]([CH2:21][CH2:22][CH3:23])[C:5]=2[O:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCCc1c2c(cc3c(=O)c(C)c(C(=O)OCC)oc13)CCCC2
Agent: Cl
Solvent: CC(=O)O
Product: CCCc1c2c(cc3c(=O)c(C)c(C(=O)O)oc13)CCCC2
Reaction time: 8 h

Procedure:
A mixture of the product of step (f) (16.2 g), glacial acetic acid (80 ml) and 5 N hydrochloric acid (20 ml) was heated and stirred on a steam bath overnight, and then evaporated. The residue was extracted with aqueous sodium bicarbonate and the extract was filtered and then acidified. Precipitated material was isolated by decantation and was triturated with water, dried, then triturated with an ether/petroleum ether (40°-60°) mixture. There remained as an insoluble off-white solid, 6,7,8,9-tetrahydro-3-methyl-4-oxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylic acid, (3.5 g), m.p 162°-4°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:17][C:18]([Cl:23])([Cl:22])[C:19](Cl)=[O:20]>C(Cl)(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]1[CH:12]=[CH:13][CH:14]=[C:15]1[C:19](=[O:20])[C:18]([Cl:23])([Cl:22])[Cl:17])[C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH3:10]
Reactant: CCOC(=O)C(C(=O)OCC)n1cccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)n1cccc1C(=O)C(Cl)(Cl)Cl
Yield: 89 %

Procedure:
To a solution of 2-(pyrrol-1-yl)malonic acid diethyl ester (100.0 g) in chloroform (100 ml) was added trichloroacetyl chloride (161.4 g), and the resulting mixture was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium carbonate solution and then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (146.4 g, 89.0%) as colorless crystals, mp 67°-69° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[C:30]1([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:39]([CH2:38][CH2:37][CH2:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: NCCCc1ccccc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(CCCc2ccccc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 3-Phenyl-propylamine. MS (ESI): 447.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][C:18]#[N:19]>>[CH3:15][C:12]1[N:13]([CH2:17][C:18]#[N:19])[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: N#CCBr
Product: Cc1cc(C#Cc2cn(CC#N)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=237.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and bromoacetonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C([O:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=1)=O)C>ClCCl>[CH3:30][C:28]1[N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:26]=[C:25]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:15][N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:22])[CH:29]=1
Reactant: CCOC(=O)c1cc(C)n(-c2ccccc2)n1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C3CN4CCSC4=N3)c2)nn1-c1ccccc1
Yield: 68.7 %

Procedure:
To 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (1.9 g, 8.7 mmol) in dry dichloromethane (40 ml) under nitrogen at room temperature was added trimethylaluminium (6 ml: 25% in hexane). After 20 min 5-methyl-1-phenylpyrazole 3-carboxylic acid ethyl ester (2 g, 8.7 mmol) in dry dichloromethane (5 ml) was added and the mixture heated under reflux for 3 days. The reaction was quenched by the slow addition of hydrochloric acid (20 ml, 2 N aqueous), basified with aqueous ammonia solution (5 N) and extracted with chloroform (3×200 ml). After drying the organic phase was concentrated in vacuo to afford an oil which was separated by column chromatography on alumina eluting with chloroform to afford the amide (2.41 g; 69%). Addition of isopropanolic hydrogen chloride gave the hydrochloride salt (1.56 g) recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4[C:15]3=O)=[CH:11][N:10]=[C:9]2[CH2:25][N:26]([CH3:28])[CH3:27])=[C:4](C(=O)C2C=CC=CC=2F)[CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]3[C:9]([CH2:25][N:26]([CH3:27])[CH3:28])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]=[C:15]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:6]=2[CH:7]=1
Reactant: CN(C)Cc1ncc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(F)cc1C(=O)c1ccccc1F
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ncc2n1-c1ccc(F)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 4, N-[[1-[4-fluoro-2-(o-fluorobenzoyl)phenyl]-2-[(dimethylamino)methyl]-imidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-fluoro-6-(o-fluorophenyl)-1-[(dimethylamino)methyl]-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[CH2:33][CH2:32]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C@H:10]([NH:15][C:16](=[O:47])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[N:29]=[C:28]([NH:30][C:31]3([C:34]4[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=4)[CH2:32][CH2:33]3)[N:27]=[C:26]([O:41][CH2:42][C:43]([F:46])([F:45])[F:44])[N:25]=2)=[CH:19][CH:18]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (1 g) in CH2Cl2 (10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 16 hours. All the solvents were removed under vacuum to give (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (0.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:16]2[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Brc1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 58.8 %

Procedure:
0.5 g of 1-bromo-4-iodobenzene and 0.3 g of 1,4-dioxa-8-azaspiro[4.5]decane are placed in 10 ml of toluene and then 0.08 g of tris(dibenzylideneacetone)dipalladium(0), 0.061 g of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 0.255 g of sodium tert-butoxide are added. The reaction medium is brought to reflux of the solvent for 4 h. Ethyl acetate is subsequently added and the mixture is washed twice with water and once with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and concentrated under reduced pressure. The crude product obtained is chromatographed on silica gel, elution being carried out with a heptane/ethyl acetate (4/1) solvent mixture. 0.31 g of 8-(4-bromophenyl)-1,4-dioxa-8-azaspiro[4.5]decane is obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH3:15])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].Cl[Si:17]([CH3:20])([CH3:19])[CH3:18].CCOCC>C1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:18][Si:17]([CH3:20])([CH3:19])[O:11][C:10]([CH3:12])=[CH:9][C:8]([O:14][CH3:15])=[O:13]
Reactant: C[Si](C)(C)Cl
Reactant: COC(=O)CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)C=C(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A mixture of freshly fused ZnCl2 (1.1 g) and triethylamine (86 mL, 0.62 mol) was stirred for 1 h at room temperature. Methyl acetoacetate (40 mL, 0.37 mol) in benzene (80 mL) was added dropwise, followed by chlorotrimethylsilane (90 mL, 0.72 mol). The mixture was stirred overnight at 40° C. After cooling, ether (500 mL) was added. The mixture was stirred for 1 h and filtered through celite. Volatiles were removed in vacuo. Hexanes (200 mL) were added to the residue which was filtered through celite once again. The filtrate was concentrated to dryness and the residue was distilled through a vigreux column at 79°-82° C. (1.2 mm) to afford 57.6 g (83%) of 1 as a clear oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:30][C:31]1[S:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=1>C(#N)C.CCOC(C)=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:30][C:31]2[S:32][CH:33]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[N:35]=2)[CH2:19][CH2:18]1)=[O:14]
Reactant: COC(=O)c1csc(CCl)n1
Reactant: COc1ccc2[nH]nc(C(=O)NCC3CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Yield: 32.2 %

Procedure:
Finally, a mixture of compound 7b (637 mg, 1.96 mmoles) and potassium carbonate (813 mg, 5.88 mmoles) in acetonitrile (5 mL) was heated to reflux for 1 hour, then a solution of methyl 2-(chloromethyl)-1,3-thiazole-4-carboxylate (500 mg, 2.6 mmoles) in acetonitrile (5 mL) was added dropwise. The mixture was refluxed overnight then was cooled, diluted with EtOAc and filtered. The resulting solid was washed with water, dried and purified via flash chromatography (silica, from CHCl3 to CHCl3:MeOH 9:1) providing 280 mg (32% yield) of methyl 2-{[4-({[(5-methoxy-1H-indazol-3-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}-1,3-thiazole-4-carboxylate 7.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([CH2:19][CH3:20])[C:14](OCC)=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:13]([CH2:19][CH3:20])[C:14](=[O:15])[N:11]=1
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: CCOC(=O)C(Br)CC
Product: CCC1SC(NC2CC3CCC2C3)=NC1=O

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and ethyl 2-bromobutyrate according to Method C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:12]([C:4]2[C:5]3[O:10][CH2:9][CH2:8][O:7][C:6]=3[CH:11]=[C:2]([NH2:1])[CH:3]=2)=[O:14])[CH2:18][CH2:17]1
Reactant: Nc1cc2c(c(C(=O)O)c1)OCCO2
Reactant: CN1CCNCC1
Solvent: CO
Product: CN1CCN(C(=O)c2cc(N)cc3c2OCCO3)CC1

Procedure:
In the same manner as described in Example 2, the 7-amino-1,4-benzodioxane-5-carboxylic acid was treated with the methanol, and then the obtained carboxylic ester was reacted with N-methyl piperazine. 5[(4-methyl-1-piperazinyl)-carbonyl]-7-amino-1,4-benzodioxane was obtained (M.P.: 170° C.).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:11]=[C:10]([CH3:20])[C:7]=1[C:8]#[N:9])(=[O:5])=[O:4])[CH3:2].N.S(=O)(=O)(O)[OH:23]>O>[CH2:1]([S:3]([C:6]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[CH:11]=[C:10]([CH3:20])[C:7]=1[C:8]([NH2:9])=[O:23])(=[O:5])=[O:4])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Agent: N
Solvent: O
Product: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C(N)=O

Procedure:
A solution of 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.50 g, 1.70 mmol) in concentrated sulfuric acid (4 ml) is stirred at 100° C. for 1.5 h. After completion of reaction (monitored by TLC), the reaction mixture is diluted with water (30 ml), basified with aqueous ammonia, and extracted with ethyl acetate (3×15 ml). The organic layer is washed with water (20 ml), brine (15 ml), dried over anhydrous sodium sulfate and evaporated to get 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzamide which is used in the next step without further purification (0.50 g, 1.60 mmol, 94%).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].Cl.Cl.[CH3:28][N:29]([CH3:34])[CH:30]1[CH2:33][NH:32][CH2:31]1>>[CH3:28][N:29]([CH3:34])[CH:30]1[CH2:33][N:32]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:31]1
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C)C1CNC1
Agent: Cl
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CC(N(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-dimethylazetidin-3-amine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.37 (s, 3H) 2.77 (br. s., 6H) 4.07-4.18 (m, 1H) 4.26 (br. s., 2H) 4.52 (br. s., 1H) 4.63 (br. s., 1H) 7.70 (d, J=6.82 Hz, 1H) 7.79 (d, J=11.37 Hz, 1H) 8.19-8.26 (m, 2H) 8.43 (d, J=8.84 Hz, 1H) 8.69 (d, J=2.27 Hz, 1H); ESI-MS m/z [M+H]+ 421.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:14][CH2:13]1.[CH3:33][CH:34](O)C>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:32])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([OH:31])[CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:34][CH:33]=2)[CH2:16][CH2:17]1
Reactant: CC(C)O
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Product: CCCCc1ccc(COCC(O)CN2CCN(CC(=O)Nc3c(C)cccc3C)CC2)cc1

Procedure:
Compound 24 was prepared in a similar manner to compound 7, substituting the commercially available 4-n-bu-benzylalcohol for 2-propanol in part C. MS (M+1)=468.45