Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C.O>[CH2:25]([N:1]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (5 g, 19.30 mmol), potassium carbonate (10.70 g, 77.20 mmol) and benzyl bromide (7.90 g, 46.30 mmol) were dissolved in 120 mL of the mixture solvent of ethanol and water (V/V=5:1). The reaction solution was heated to 60° C. and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, added with 100 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, yield: 43.0%) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:42])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:32][CH2:31][C:30]([C:38]([F:41])([F:40])[F:39])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[CH2:28][CH2:29][C:30]([C:38]([F:41])([F:40])[F:39])([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)=[O:42])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)OCC)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C(=O)O)(C(F)(F)F)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)-4-(trifluoromethyl)piperidine-4-carboxylate (0.05 g, 0.08 mmol) in DMSO (2.0 mL) was added potassium tert-butoxide (0.046 g, 0.41 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (2×50 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5 then extracted with hot EtOAc (3×75 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 142 as off-white solid (0.04 g, 84% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.65 (m, 2H), 2.31 (m, 2H), 3.01 (m, 2H), 3.20 (q, J=7.20 Hz, 2H), 4.75 (m, 2H), 6.87 (br s, 1H, D2O exchangeable), 7.43 (m, 1H), 7.99 (m, 2H), 8.23 (s, 1H), 8.48 (d, J=7.20 Hz, 1H), 8.80 (d, J=3.60 Hz, 1H), 8.92 (s, 2H), 10.57 (br s, 1H, D2O exchangeable) and 14.06 (br s, 1H, D2O exchangeable). MS: 572.10 [M+H]+.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]1)[CH3:21]>C1(C)C=CC=CC=1>[CH:7]1[C:6]2[CH:5]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]3[CH2:22][N:20]([CH3:21])[CH3:19])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN(C)CC1CCCCN1
Solvent: Cc1ccccc1
Product: CN(C)CC1CCCCN1C1c2ccccc2Oc2ccccc21

Procedure:
A solution of 3.5 g. (14.6 mmoles) of 9-acetoxyxanthene and 2.1 g. (14.8 mmoles) of 2-(dimethylaminomethyl)-piperidine in 50 ml. of toluene was refluxed for 40 hours. The mixture was then washed with sodium bicarbonate, dried and evaporated. Recrystallization of the residue from hexane afforded 1-(9-xanthenyl)-2-(dimethylaminomethyl)-piperidine, m.p. 81°-83°C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]#[N:23])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COS(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O>[CH3:1][N:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[C:22]#[N:23]
Reactant: N#CNc1ccc(OCc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C#N)c1ccc(OCc2ccccc2)cc1

Procedure:
Potassium carbonate (9.6 g) was added to a solution of 4-benzyloxyphenylcyanamide (6.3 g) in acetone (450 ml) with stirring. A solution of methyl-4-toluene sulphonate (9 g) in acetone (50 ml) was added and the mixture stirred for 7 hours. The solvent was removed by evaporation and the residue suspended in water and extracted into dichloromethane. The extract was dried (Na2SO4) and the solvent removed by evaporation to give a residue which was triturated with a 1:1 mixture of ethylacetate and hexane to give N-methyl-4-benzyloxyphenylcyanamide (m.p. 116° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7][C:8](=[O:12])O[C:10](=[O:11])[C:5]=2[CH:4]=1.[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][NH:20][CH2:21]C(O)=O>CC1C=CC(C)=CC=1>[CH3:15][O:16][C:17]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:18]=1[CH2:19][N:20]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([S:2][CH3:1])[CH:14]=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:21]1
Reactant: CSc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(SC)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-methylsulfanyl-1H-benzo[d][1,3]oxazine-2,4-dione (4.8 g, 23 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (5.6 g, 25 mmol) in p-xylene (50 mL) was heated under reflux (150° C.) for 3 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2×20 ml). Yield: 7.5 g (89%). m/z 373 (MH+).
Reaction SMILES: [CH:1]1([S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([NH2:10])=O)[CH2:4][CH2:3][CH2:2]1.B.C1COCC1.[ClH:21]>C1COCC1>[ClH:21].[CH:1]1([S:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[CH2:8][NH2:10])[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccccc1SC1CCC1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccccc1SC1CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 2C (5.00 g, 20.9 mmol) in THF (80 mL) at reflux was added a 1M THF solution of BH3.THF (63 mL, 62.7 mmol) via an addition funnel, dropwise over 20 min. After refluxing for 6 h, additional BH3.THF solution was added (20 mL) and refluxing continued overnight. After cooling to rt, 6N HCl (12.5 mL) was added and the reaction was heated again to reflux for 1 h. The reaction was cooled to rt, concentrated then azeotroped (3×) with MeOH/THF. After drying under vacuum for 1 h, the resulting residue was taken up in THF and filtered to provide 2D as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.94-2.11 (m, 2H), 2.13-2.26 (m, 2H), 2.43-2.61 (m, 2H), 4.11-4.23 (m, 1H), 4.43 (s, 2H), 7.66-7.76 (m, 2H), 7.81 (t, J=6.81 Hz, 1H), 8.03 (d, J=6.15 Hz, 1H). LC-MS: 226.11 (M+H)+.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=[C:11]([Br:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+]=[N-].CP(C)C.[ClH:20]>O1CCCC1.C(#N)C>[ClH:20].[Br:14][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Br:15])[CH:10]=1)[O:7][CH2:6][CH2:5][C@H:4]2[NH2:1]
Reactant: [N-]=[N+]=N[C@@H]1CCOc2c(Br)cc(Br)cc21
Agent: CP(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Product: N[C@@H]1CCOc2c(Br)cc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an ice cooled solution of 4(R)-azido-6,8-dibromo-chroman in tetrahydrofuran (0.16M) was added 1.2 equivalents of trimethylphosphine. The mixture was warmed to room temperature and maintained for 16 h. Concentration of the mixture gave the crude amine. This was dissolved in acetonitrile (0.20M) and 2 equivalents of hydrochloric acid added. The mixture was stirred for 16 h and the solids filtered, washed with acetonitrile and dried to afford the title compound as an off-white solid.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[SH:15])=O)(C)(C)C>C(O)=O>[N:8]1[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[S:15][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccncc1S
Solvent: O=CO
Product: c1cc2ncsc2cn1
Yield: 45.2 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]-3-mercaptopyridine (33.2 g) was dissolved in formic acid (250 ml), and the solution was heated under reflux for 3 days. The reaction mixture was concentrated under reduced pressure, and a 5N aqueous solution (100 ml) of potassium hydroxide and ether were added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=25:1) to obtain the title compound (9.03 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)CC[CH2:14]1)=[O:12].[CH3:28][O:29]C1C=CC=CC=1NC>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([N:13]([C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:29][CH3:28])[CH3:14])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: CNc1ccccc1OC
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccccc1N(C)C(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 2-methoxy-N-methylaniline (commercially available; CAS RN 10541-78-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60). The compound was further purified through a second preparative HPLC chromatography (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5). White solid (57%). MS (ESI): m/z=403.062 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([C@@H:29]2[CH2:31][O:30]2)[CH:26]=[CH:27][CH:28]=1>C(O)C>[CH2:1]([N:8]([CH2:31][C@@H:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=1)[OH:30])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)c1cccc(Cl)c1)CCC2
Yield: 86.1 %

Procedure:
A mixture of N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (0.30 g) and (R)-3-chlorophenyl oxirane (0.18 g) in ethanol (0.6 ml) was refluxed overnight. The reaction mixture was evaporated in vacuo, and the residue was purified by column chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (5:1). The product (0.43 g) was treated with 4N hydrogen chloride in ethyl acetate and powdered from diisopropyl ether to afford (1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol (0.40 g).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:3][CH2:4][NH2:5].[C:21]([NH:23][C:24](=[N:32][CH2:33][CH2:34][S:35][CH2:36][C:37]1[N:38]=[C:39]([NH:42][C:43]([NH2:45])=[NH:44])[S:40][CH:41]=1)OC1C=CC=CC=1)#[N:22]>>[C:21]([NH:23][C:24]([NH:32][CH2:33][CH2:34][S:35][CH2:36][C:37]1[N:38]=[C:39]([NH:42][C:43]([NH2:45])=[NH:44])[S:40][CH:41]=1)=[N:5][CH2:4][CH2:3][N:2]([CH2:6][CH2:7][CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:1])#[N:22]
Reactant: CN(CCN)CCC(c1ccccc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCN=C(NC#N)NCCSCc1csc(NC(=N)N)n1)CCC(c1ccccc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.8 g (3 mmol) of N-methyl-N-[3-phenyl-3-(2-pyridyl)propyl]-1,2-ethanediamine and 1.01 g (2.7 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int.[%])=551 ([M+H]+, 2), 196 (100); IR (KBr): 2164 cm-1 (C≡N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 115°-116° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].FC1C=CC(OC)=CC=1C=O.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cc(O)ccc1F
Agent: BrB(Br)Br
Agent: COc1ccc(F)c(C=O)c1
Solvent: ClCCl
Product: OCc1cc(O)ccc1F
Reaction time: 3 h

Procedure:
2-Fluoro-5-hydroxybenzyl alcohol was prepared according to the following procedure: 2-Fluoro-5-hydroxybenzaldehyde: to a stirred solution of 2-fluoro-5-methoxybenzaldehyde (18.3 g) in dichloromethane (200 mL) at 0° C. was added dropwise a solution of boron tribromide in dichloromethane (1M, 120 mL, 1 eq.). The mixture was stirred for 3 h then concentrated to a volume of ˜50 mL and partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was washed (water), dried (magnesium sulfate) and concentrated to give a red oil (22.7 g). The oil was purified by column chromatography (SiO2, DCM→DIPE) to give the product as a pink crystalline solid (9.9 g, 59% yield);
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH3:17])[C:4](=[O:18])[CH:3]=1.CN.FC1C=C(I)C=C[C:23]=1[N:29]1C(=O)C=C(NC)N(C)C1=O>CO>[F:15][C:9]1[CH:10]=[C:11]([I:14])[CH:12]=[CH:13][C:8]=1[N:7]1[C:2]([NH:29][CH3:23])=[CH:3][C:4](=[O:18])[N:5]([CH3:17])[C:6]1=[O:16]
Reactant: Cn1c(=O)cc(Cl)n(-c2ccc(I)cc2F)c1=O
Reactant: CNc1cc(=O)n(-c2ccc(I)cc2F)c(=O)n1C
Agent: CN
Solvent: CO
Product: CNc1cc(=O)n(C)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.9 %

Procedure:
To a 6:5 mixture (75.7 g) of 6-chloro-1-(2-fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65 and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyrimidine-2,4-dione 66 obtained in Step 3 were added methanol (227 ml) and 40% solution (152 ml) of methylamine in methanol, and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was concentrated under reduced pressure, and toluene (150 ml) and water (150 ml) were added to the residue, and the mixture was stirred under heating at reflux for 30 min. After allowing to return to room temperature, the crystals were collected by filtration and dried to give a 6:5 mixture (59.6 g, yield 79.9%) of 1-(2-fluoro-4-iodophenyl)-3-methyl-6-methylamino-1H-pyrimidine-2,4-dione 67 and 3-(2-fluoro-4-iodophenyl)-1-methyl-6-methylamino-1H-pyrimidine-2,4-dione 68 as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.I[CH2:15]I>O1CCCC1.[Zn].CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH2:15])[CH:9]=[CH:10][CH:11]=1
Reactant: ICI
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of one mole equivalent of m-trifluoromethoxybenzaldehyde in dry tetrahydrofuran is combined with 5 mole equivalents of diiodomethane, 9 mole equivalents of zinc powder, 1 mole equivalent of titanium tetraisopropoxide, and the mixture is stirred at room temperature for 3 hours. The product is extracted from the mixture after removal of solvent in vacuo to give m-trifluoromethoxyphenylethene.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Cl)cc3)cs2)cc1

Procedure:
A mixture of 0.3 g of 4-(4-chlorophenyl)-thiazol-2-ylamine hydrobromide with 0.22 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a hot mixture of 20 ml of ethanol and 30 ml of water. 0.05 g of N-[4-(4-chlorophenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon cooling.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[CH3:87][N:88]([CH3:94])[C:89](=[O:93])[C:90](O)=[O:91]>>[CH3:87][N:88]([CH3:94])[C:89](=[O:93])[C:90]([NH:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1)=[O:91]
Reactant: CN(C)C(=O)C(=O)O
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 13 %

Procedure:
The title compound was prepared in 13% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except N,N-dimethyloxamic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 627.6 (M−H)−, 1.91 min (method 5). 1H NMR (500 MHz, 2:1 MeOD:CDCl3) δ=7.93 (d, J=8.2 Hz, 2H), 7.55 (s, 1H), 7.21 (d, J=8.2 Hz, 2H), 5.30 (dd, J=1.7, 6.3 Hz, 1H), 4.77 (d, J=1.2 Hz, 1H), 4.65 (s, 1H), 3.22 (s, 3H), 3.01 (s, 3H), 2.71-2.59 (m, 2H), 2.46 (dd, J=8.2, 11.9 Hz, 1H), 2.14 (dd, J=6.3, 17.2 Hz, 1H), 2.02-1.93 (m, 1H), 1.89 (dt, J=3.4, 12.2 Hz, 1H), 1.79 (d, J=13.1 Hz, 1H), 1.75 (d, J=3.7 Hz, 1H), 1.71 (br. s., 1H), 1.66 (dt, J=3.5, 13.5 Hz, 1H), 1.61-1.54 (m, 2H), 1.54-1.48 (m, 4H), 1.46 (br. s., 1H), 1.45-1.40 (m, 3H), 1.40-1.34 (m, 1H), 1.28 (br. s., 2H), 1.20-1.14 (m, 2H), 1.13 (s, 3H), 1.05 (s, 3H), 1.03 (s, 3H), 0.96 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH2:47][CH2:48][CH2:49][NH:50][C:51]1[N:56]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:54]=[C:53]([NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:70])[CH3:69])[CH:52]=1>CN1C(=O)CCC1>[C:68]([NH:67][CH2:66][CH2:65][NH:64][C:53]1[N:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[N:56]=[C:51]([NH:50][CH2:49][CH2:48][NH:47][C:1]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:13])[CH:52]=1)(=[O:70])[CH3:69]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(=O)NCCNc1cc(NCCN)nc(-c2ccc(Cl)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)NCCNc1cc(NCCNC(=O)c2ccc3ccccc3n2)nc(-c2ccc(Cl)cc2)n1
Reaction time: 48 h

Procedure:
A solution of quinaldic acid (60 μl of a 0.3M solution in NMP), HATU (60 μl of a 0.3M solution in NMP) and diisopropylethylamine (60 μl of a 0.3M solution in NMP) was shaken at ambient temperature in a well of a 96 position microtitre plate for 5 min. N-(2-{[6-[(2-aminoethyl)amino]-2-(4-chlorophenyl)pyrimidin-4-yl]amino}ethyl) acetamide (30 μl of a 0.3M solution in NMP) was then added and the mixture shaken for a further 48 hrs. Purification via ion exchange silica (SCX) yields the title compound. LCMS (Method A) RT=2.58 min; m/z (ES+) 504 (MH)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:19][CH:20]([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C(#N)C.C(=O)(O)[O-].[Na+]>>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:26][C:25]4[CH:27]=[CH:28][C:22]([O:21][CH:20]([F:19])[F:29])=[CH:23][CH:24]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(OC(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2Cl)C3)cc1
Temperature: 160 °C
Yield: 76.5 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.103 g, 0.000366 mol) and 4-(difluoromethoxy)aniline (0.091 mL, 0.00073 mol) in acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 160° C. for 10 minutes. After cooling to room temperature, the mixture was added to saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.113 g of a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH:10]C(OC(C)(C)C)=O)=[O:8])=[N:4][CH:3]=1.Cl>CO>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[N:4][CH:3]=1
Reactant: Cc1cnc(C(=O)NNC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CO
Product: Cc1cnc(C(=O)NN)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1,1-dimethylethyl 2-[(5-methyl-1,3-thiazol-2-yl)carbonyl]hydrazinecarboxylate (I116)(451 mg, 1.753 mmol) in HCl (2.191 ml, 72.1 mmol) (4M solution in 1,4-dioxan) was stirred at room temperature under an atmosphere of argon for 18 hours. After this time, the solvent was removed under reduced pressure to give an off white coloured solid. The solid was dissovled in MeOH and passed through an SCX cartridge, washing first with MeOH and then with 2M NH3 in MeOH The NH3 containing fractions were combined and concentrated under reduced pressure to give a white coloured solid of desired product in 224 mg.