Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:13][CH:12]=3)=[CH:5][CH2:4]1.Br.[Sn]>>[CH3:30][N:2]([CH3:1])[C:3]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH3:18])=[CH:15][C:14]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Agent: Br
Agent: [Sn]
Product: Cc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccc(OC(F)(F)F)cc12
Reaction time: 1.5 h

Procedure:
(±)-N,N-Dimethyl-N-[4-(3-methyl-5-trifluoromethoxy-1H-indol-2-yl)-1-phenylcyclohex-3-enyl]amine (350 mg, 0.84 mmol) was stirred with HBr/glacial acetic acid (33% HBr, 18 ml) until it had dissolved completely. Tin powder (0.98 g, 8.4 mmol) was then added to the mixture in portions in the course of 30 min. When the addition had ended, the reaction mixture was stirred for a further 1.5 h, and for working up it was then concentrated to dryness on rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (40 ml). The solution obtained was extracted with methylene chloride (4×30 ml). The combined organic phases were dried with Na2SO4 and then concentrated. The residue (410 mg) was separated by column chromatography [silica gel 60 (30 g); ethyl acetate/cyclohexane (1:1; 500 ml); ethyl acetate/methanol (2:1, (450 ml)]. N,N-dimethyl-4-(3-methyl-5-(trifluoromethoxy)-1H-indol-2-yl)-1-phenylcyclohexanamine (less polar diastereoisomer) was obtained in a yield of 132 mg (38%) as a colourless solid with a melting point of 78-84° C. The more polar diastereoisomer was obtained in a yield of 151 mg (43%) as a colourless solid with a melting point of 219-221° C.
Reaction SMILES: C([Mg]Cl)(C)C.[NH2:6]/[C:7](=[N:9]\[O:10][C:11]([C:13]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=O)/[CH3:8]>C1COCC1>[F:23][C:22]1[C:13]([C:11]2[O:10][N:9]=[C:7]([CH3:8])[N:6]=2)=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1cccc(F)c1C(=O)O/N=C(/C)N
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1noc(-c2c(F)cccc2C(=O)O)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To THF (15 mL) was added 2 M i-PrMgCl in THF (2.2 mL, 4.47 mmol). This mixture was cooled to −78° C. and the product of Step B (1.09 g, 3.58 mmol) was added dropwise in THF (20 mL). The mixture was stirred for 30 min at −78° C. and then CO2 from a lecture bottle was bubbled into the solution for 3 h while allowing the temperature to slowly rise. When the temperature reached −20° C. the dry ice bath was replaced with an ice bath, bubbling of CO2 was ceased and the mixture was allowed to come to room temperature overnight. The mixture was quenched by the addition of H2O and a small amount of Et2O. The organic layer was washed 2× with 2 N NaOH and the combined aqueous layers were then washed 3× with Et2O. The aqueous layer was then acidified with concentrated HCl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product as a white solid (661 mg, 83%). MS (ESI) mass calculated for C10H7FN2O3, 222.04; m/z found, 223.0. 1H NMR (500 MHz, CDCl3): 7.96 (d, J=7.8, 1H), 7.72-7.64 (m, 1H), 7.50-7.44 (m, 1H), 2.56-2.48 (m, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:10]=1[CH2:11][NH:12][C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][CH:18]=1>O1CCCC1>[NH2:20][CH2:19][C:14]1[C:13]([NH:12][CH2:11][C:10]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:9]=2[O:8][CH3:7])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CNc2cccnc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccnc2CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 13.3 mL, 13.3 mmol) was added slowly to a solution of 3-[(2,4-dimethoxybenzyl)amino]pyridine-2-carbonitrile (3.25 g, 12.1 mmol) in tetrahydrofuran (40 mL) at 0° C. The reaction was warmed to room temperature and stirred for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.68 g). MS 274.3 (M+1).
Reaction SMILES: [SH:1][C:2]1([CH2:12][C:13](OC(C)(C)C)=[O:14])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2>ClCCl>[SH:1][C:2]1([CH2:12][CH2:13][OH:14])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC(C)(C)OC(=O)CC1(S)C2CC3CC(C2)CC1C3
Solvent: ClCCl
Product: OCCC1(S)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60.6 %

Procedure:
To a 0° C. cooled solution tert-butyl 2-(2-sulfanyladamantan-2-yl)acetate (4.1 g, 24.1 mmol) in anhydrous dichloromethane (40 mL) lithium aluminum hydride (1 M solution in THF) (40 mL) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at 0° C. for further 15 minutes and then at room temperature for 30 minutes. The excess LiAlH4 was destroyed by the addition of ethyl acetate. The reaction mixture was then poured over ice cold water, acidified with 1 N HCl and extracted with dichloromethane (2×200 mL). The combined extracts were washed with brine (1×75 mL), dried over sodium sulfate, filtered and solvent evaporated at reduced pressure to give the title compound (3.1 g), mp 68-70° C.; 1H NMR (CDCl3): δ1.16-1.9 (m, 11H), 2.1 (m, 2H), 2.22 (t, J=6.9 Hz, 3H), 2.43 (m, 2H), 3.93 (t, J=6.9 Hz, 2H); 13C NMR (CDCl3): δ26.8, 27.7, 33.2, 33.9, 38.2, 39.1, 43.4, 55.8, 59.4; LRMS (APIMS) (m/z) 230 (M+18) (M+NH4).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1>>[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH2:1][CH2:2][CH3:3])=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: CCC=O
Product: CCCNc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 8, react propanaldehyde with 4-(1H-imidazol-1-yl)benzenamine to obtain the title compound.
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC(C3C=C([C:17](O)=[O:18])C=NC=3)=CC=2N=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH:17]=[O:18])[CH2:29][CH2:28]1
Reactant: O=C(O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN1CCNCC1
Product: CN1CCN(C=O)CC1

Procedure:
5-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylic acid (40 mg) was reacted with 1-methylpiperizine via General Procedure B to yield 5-(2-chloro-4-morpholinothieno[3,2-d]-pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone. Crude 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-yl)(4-methylpiperazin-1-yl)methanone (48 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 14.6 mg of 348. MS (Q1) 541.1 (M)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.O>CN(C=O)C>[CH2:7]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][OH:15])[CH2:18][CH2:19]1)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)C1CCC(CO)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (2.61 g, 18.9 mmol) and benzyl bromide (2.24 mL, 18.9 mmol) were added to a solution of 4-hydroxymethyl-cyclohexanecarboxylic acid (cis-trans=2.9:1 mixture) (2.49 g, 15.7 mmol) in DMF (31.5 mL) at room temperature, and the mixture was stirred at 60° C. for one hour. The reaction solution was cooled, and H2O (60 mL) was then added to the reaction solution, followed by extraction with hexane:ethyl acetate (2:1) (300 mL) twice. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=3.5:1 mixture) as a colorless oily substance (3.79 g, 97%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C=O)C>[CH3:25][S:26]([O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@:4]1([OH:16])[CH3:17])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
A solution of (1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (12 g, 50 mmol) in anhydrous DMF (100 mL) was cooled with an ice bath under N2. To this mixture, triethylamine (15 mL, 110 mmol) and methanesulfonyl chloride (5.0 mL, 60 mmol) was added. The ice bath was removed and the mixture stirred at room temperature for 3 h. The reaction was diluted with diethyl ether and washed with 1 M HCl, saturated aqueous sodium bicarbonate and brine. The organic layer was concentrated to dryness to yield [(1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyl-decahydronaphthalen-1-yl]-methyl methanesulfonate (12) (15 g, 97% yield) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:44])[F:45])=[CH:39][CH:38]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-(trifluoromethyl)-benzenesulfonyl chloride. Purity (ELSD, based on MW=629.6)=94%.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Mg].Br[CH:3]=[CH:4][CH3:5].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C:12](=[CH:14][CH:15]=[O:16])[CH3:13])[CH3:8].[NH4+].[Cl-]>O1CCCC1>[CH3:13][C:12]([CH2:11][CH2:10][CH:9]=[C:7]([CH3:6])[CH3:8])=[CH:14][CH:15]([OH:16])[CH:3]=[CH:4][CH3:5]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CC=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C=C(C)CCC=C(C)C
Reaction time: 8 h

Procedure:
12 g. of magnesium turnings were suspended under nitrogen in 250 ml. of dry tetrahydrofuran. Between 60° and 65°, 60 g. of 1-bromopropene dissolved in 50 ml. of tetrahydrofuran were added dropwise. During the addition, to prevent escaping of 1-bromopropene, the reflux condenser fitted on the reaction flask was cooled to -40°/-50°. When all Mg had reacted, the mixture was cooled to 20° and 76 g. of citral was added dropwise with cooling. After standing overnight, the mixture was poured into 1.5 liter of concentrated aqueous NH4Cl at 0°. The mixture was extracted 3 times with ether and the combined ether extracts treated as usual. After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene, b.p. 70°/0.1 Torr was obtained as a liquid with following constants : nD20 =1.4950; d420 =0.9145.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Cl.[F:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:23]2[CH2:24][CH2:25][CH:20]([F:19])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: FC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1N1CCC(F)CC1
Temperature: 40 °C
Yield: 100.1 %

Procedure:
A solution of 4-chloro-2-fluoro-1-nitro benzene (0.30 g, 1.7 mmol) in toluene (5 mL) was treated with solid Na2CO3 (0.40 g, 3.7 mmol) and 4-fluoropiperidine hydrochloride (0.25 g, 1.8 mmol). The reaction was heated to 40° C. for 6 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (0.44 g, 99%) as a bright yellow oil. 1H-NMR (CDCl3; 400 MHz): δ 7.79 (d, 1H, J=8.8 Hz), 7.10 (d, 1H, 2.0 Hz), 6.97 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 4.97-4.79 (m, 1H), 3.26-3.17 (m, 2H), 3.06-2.99 (m, 2H), 2.14-1.97 (m, 4H). LC-MS (ESI, m/z): Calcd. for C11H12ClFN2O2, 225.2 (M-Cl+2H), found 225.2.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13](Br)[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([C:34]([NH:36][C:37]1[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:38]=1[O:52][CH3:53])=[O:35])[N:28]2[CH3:33]>>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([C:40]3[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:27]4[N:28]([CH3:33])[C:29]5[C:25]([CH:26]=4)=[C:24]([O:23][CH3:22])[CH:32]=[CH:31][CH:30]=5)=[O:35])=[C:38]([O:52][CH3:53])[CH:39]=3)[N:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: CC(=O)O[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](OC(C)=O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
Using the procedure described in example 1 step 1f (trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (0.568 mmol, 200 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (0.568 mmol, 248 mg) gave after purification using column chromatography (silica gel; gradient heptanes/ethyl acetate 1/1 to ethyl acetate) the title compound (245 mg).
Reaction SMILES: [CH2:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[CH2:1]([C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCc1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To 70 mL of dehydrated dichloromethane, 24.68 g (100 mmol) of n-dodecylbenzene was added and 36.82 g (189 mmol) of titanium tetrachloride was gradually added in drops. The reaction system kept below 10° C. in an ice bath and 13.16 9 (114 mmol) of 1,1-dichloromethl methy ether added in drops thereto were stirred together below 10° C. for 30 minutes and further stirred at a room temperature for 45 minutes. The resultant reaction mixture was added to 500 mL of ice water. It was extracted four times with 200 mL of dichloromethane and dried overnight on sodium sulfate. The solvent was removed by the use of an evaporator and purified by column chromatography (silica gel, benzene:hexene =1:1). Consequently, 11.22 g (40.2 mmol) of a light yellow slightly viscous liquid was obtained. The yield was 40%.
Reaction SMILES: [Na+].[C:2]1([S:8]([O-:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH:17]=1.Cl>O>[CH3:11][CH:12]1[CH:17]([S:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:10])=[O:9])[CH2:16][CH2:15][CH2:14][C:13]1=[O:18]
Reactant: O=S([O-])c1ccccc1
Reactant: CC1=CCCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1C(=O)CCCC1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
Benzenesulfinic acid sodium salt (2.9 g) was added to a solution containing 1.5 g of 2-methyl-2-cyclohexen-1-one and 8 ml of water. Then 16 ml of 1N hydrochloric acid was added dropwise to the resulting mixture. The reaction mixture was stirred at room temperature for 24 hours. The crystals so precipitated were filtered and then, washed with water, isopropanol and cold ethyl ether. After recrystallization from isopropanol, 2-methyl-3-(phenylsulfonyl)-cyclohexan-1-one was obtained in the form of white crystals. Yield: 93%, TLC: (hexane-AcOEt: 6-4) Rf=0.25
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[C:8]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:9].[H-].[Na+].S(OC)(O[CH3:28])(=O)=O.N>CN(C)P(=O)(N(C)C)N(C)C.O>[CH3:28][O:9]/[C:8](/[C:7]1[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:19]=[CH:20][CH:21]=[C:2]([CH3:1])[CH:3]=1)=[CH:10]/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CC(=O)c1ccccc1Oc1cccc(C)c1
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)/C=C(/OC)c1ccccc1Oc1cccc(C)c1
Yield: 22.3 %

Procedure:
A solution of 5 g (18 mmol) of methyl 2-(3-methylphenoxy)benzoylacetate in 30 ml of hexamethylphosphoric triamide (HMPT) is added dropwise to a suspension of 500 mg (21 mmol) of sodium hydride in 20 ml of HMPT, and the mixture is stirred until evolution of gas ceases. Then 2.5 g (20 mmol) of dimethyl sulfate are added dropwise, the mixture is stirred for 30 min, and then 30 ml of concentrated ammonia solution are added. The mixture is poured into water and extracted with MTB ether. The organic phase is dried and concentrated. Chromatography of the residue on silica gel with hexane/MTB ether yields in the first fractions 1.2 g (22%) of methyl (E)-β-methoxy-2-(3-methylphenoxy)cinnamate (trans product) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].S([CH2:22][N+:23]#[C-:24])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:24]=[N:23][CH:22]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc(-c2cnco2)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
The mixed solution of 3-bromo-4-methoxybenzaldehyde (200 mg, 0.93 mmol) in methanol (4 mL) was added tosylmethyl isocyanide (200 mg, 1.02 mmol) and K2CO3 (260 mg, 1.88 mmol). The reaction was stirred at room temperature for 5 min before heated to 80° C. in the sealed tube. After 30 min, the solution was cooled to room temperature and concentrated. Column chromatography afforded 5-(3-bromo-4-methoxyphenyl)oxazole (o) (190 mg, 80%). Following the procedures analogous to the Suzuki and amide coupling reactions described for Compound 20, Compound 25 was prepared.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10]>>[CH3:7][N:8]([CH3:13])[S:9]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:11])=[O:10]
Reactant: O=C1NCCN1
Reactant: CN(C)S(=O)(=O)Cl
Product: CN(C)S(=O)(=O)N1CCNC1=O

Procedure:
The starting material required for the above reaction is prepared as follows: A mixture of 17.2g of ethylene urea and 28.7 g of N,N-dimethyl sulphamoyl chloride is heated at 110° for 3 hours. The reaction mixture is cooled and triturated with 100 ml methanol. Some solid material separated which is discarded. The filtrate is evaporated off to dryness and the residue is dissolved in 5% methanol in chloroform and chromatographed on a column of 150 g of silica gel. The fraction which eluted with 2% methanol in chloroform is recrystallised from a mixture of methylenechloride and hexane to give 1-(N,N-dimethylsulphamoyl)-2-oxo-tetrahydroimidazole which melts at 129°.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][NH:9][C:10]2[CH2:14][CH:13]([CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]4)[O:12][N:11]=2)=[CH:6][CH:5]=1.N1C=CN=C1.II>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:30][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]2[CH:14]=[C:13]([CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]=[CH:20]4)[O:12][N:11]=2)=[CH:28][CH:29]=1
Reactant: O=C1CCc2cc(OCC3CC(NCc4ccc(OC(F)F)cc4)=NO3)ccc2N1
Agent: II
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=c1ccc2cc(OCc3cc(NCc4ccc(OC(F)F)cc4)no3)ccc2[nH]1
Temperature: 110 °C
Yield: 19.4 %

Procedure:
Into a sealed tube was placed a solution of 6-((3-((4-(difluoromethoxy)benzyl)amino)-4,5-dihydroisoxazol-5-yl)methoxy)-3,4-dihydroquinolin-2(1H)-one (0.12 g, 0.287 mmol), imidazole (0.117 g, 1.725 mmol), and iodine (0.219 g, 0.862 mmol) in toluene (5 mL). The tube was sealed and heated at 110° C. for 24 h. The reaction mixture was diluted with ethyl acetate, washed with 10% Na2S2O4 and brine, dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC on an Xbridge phenyl column (150×19×5μ) using a 10 mM NH4OAc/ACN gradient (0-100%) to give 6-((3-(4-(difluoromethoxy)benzylamino)isoxazol-5-yl)methoxy)quinolin-2(1H)-one as a white solid (0.023 g, 23%). 1HNMR: 400 MHz, DMSO-d6: δ 4.24 (d, J=6.00 Hz, 2H), 5.11 (s, 2H), 6.06 (s, 1H), 6.51 (d, J=9.20 Hz, 1H), 6.73 (t, J=6.00 Hz, 1H), 7.01-7.39 (m, 8H), 7.83 (d, J=9.60 Hz, 1H), 11.66 (s, 1H). LCMS: RT 1.558 min; LCMS (ES-API), m/z 412.0 (M−H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>ClCCl>[CH2:40]([O:39][C:37](=[O:38])[NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[CH:8][C:7]=1[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1)[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCOc1ccc(NC(=O)c2cccc(OC)c2)cc1-c1ccnn1C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
The N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide hydrochloride (30.0 mg, 74.5 μmol) and triethylamine (31.1 μL, 3.0 eq) were taken up in 2 mL of dichloromethane and stirred for 15 mins. To this was added ethyl chloroformate (8.58 μL, 1.2 eq) and the reaction was stirred at room temperature for 18 hrs. The solvents were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 52.4% yield. LCMS m/z (%)=439 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 1.23 (t, J=7.07 Hz, 3 H), 3.44-3.51 (m, 2H), 3.85 (s, 3 H), 3.88 (s, 3 H), 3.94-4.21 (m, 5 H), 6.38 (d, J=2.53 Hz, 1 H), 7.03 (d, J=9.60 Hz, 1 H), 7.11 (dt, J=4.67, 2.27 Hz, 1 H), 7.36-7.46 (m, 3 H), 7.62-7.72 (m, 2 H), 7.83 (s, 1H)