Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([S:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][N:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[S:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: BrCCCCCCC(Sc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccccc1)c1ccccc1)CC2
Yield: 36.4 %

Procedure:
The free base from 4.60 g of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride, 3.63 g of [(7-bromo-1-phenylheptyl)thio]benzene, 50 ml of acetonitrile and 2.61 ml of ethyl diisopropylamine is heated at reflux temperature for 29 hours. The solvent is evaporated over night and the residue is partitioned between chloroform and aqueous ammonium hydroxide. The organic layer is dried and concentrated in vacuo to give 5.81 g of crude product. The residue is purified by chromatography (silica gel: chloroform/methyl alcohol) to give 1.73 g of the desired product.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH:9]([C:16]1[C:21]([Br:22])=[CH:20][N:19]=[C:18]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C>O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:18]2[N:17]=[C:16]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:21]([Br:22])=[CH:20][N:19]=2)=[CH:25][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reaction time: 2 h
Yield: 70.2 %

Procedure:
Sodium hydrosulphite (9.5 g, 54.5 mmol) was added over 30 minutes to a stirred solution of anilino-5-bromo-2-(4-nitroanilino)pyrimidine (Method 39; 7.0 g, 18.2 mmol) in a hot mixture of ethanol and water (1:1, 100 ml). The resulting suspension was stirred for a further two hours and insoluble material was removed by filtration. The filtrate was concentrated and the residue was partitioned between 1M aqueous sodium hydroxide (50 ml), and DCM (100 ml). The organic layer was separated, washed with water (2×10 ml) and dried. Volatile material was removed by evaporation to give the product (4.55 g, 70%). MS (MH+): 356, 358.
Reaction SMILES: [CH:1]1([N:4]([C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[F:18])C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1>>[Cl:26][C:23]1[CH:22]=[N:21][C:20]([N:15]2[CH2:16][CH2:17][C@@H:12]([NH:4][CH:1]3[CH2:2][CH2:3]3)[C@@H:13]([F:18])[CH2:14]2)=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(C1CC1)[C@@H]1CCNC[C@@H]1F
Reactant: Clc1cnc(Cl)nc1
Product: F[C@H]1CN(c2ncc(Cl)cn2)CC[C@H]1NC1CC1

Procedure:
The title compound is prepared from tert-butyl N-cyclopropyl-N-[(3S,4R)-3-fluoropiperidin-4-yl]carbamate and 2,5-dichloropyrimidine following a procedure analogous to that described for Intermediate 87. LC (method 20): tR=1.86 min; Mass spectrum (APCI): m/z=271 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]2[C:22](=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)[C:21]1[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=1[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1.[Br:33]Br>C(O)(=O)C>[Br:33][C:31]1[CH:30]=[CH:29][C:21]2[C:22]3[C:13]([C:14]4[C:19]([C:20]=2[CH:32]=1)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[C:28]1[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]1
Reactant: BrBr
Reactant: c1ccc2cc(-c3cc4c5ccccc5c5ccccc5c4c4ccccc34)ccc2c1
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)c1ccccc1c1cc(-c3ccc4ccccc4c3)c3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
4.05 g of 10-(2-naphthyl)benzo[g]chrysene and 400 mL of acetic acid were placed in a flask. 1.92 g of bromine was added, and the resultant was heated with stirring at 100° C. for 8 hours. After cooling to room temperature, the reaction solution was poured to 1 L of ice water. Deposited solids were separated by filtration, and washed with water and then with methanol, and dried. The thus obtained solids were purified by means of silica gel column chromatography, whereby 4.35 g (yield: 90%) of 3-bromo-10-(2-naphthyl)benzo[g]chrysene was obtained.
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[C:5](Br)=[N:6][CH:7]=[CH:8][CH:9]=1.[CH:12]1(B(O)O)[CH2:14][CH2:13]1>>[F:1][CH:2]([F:11])[O:3][C:4]1[C:5]([CH:12]2[CH2:14][CH2:13]2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)Oc1cccnc1Br
Reactant: OB(O)C1CC1
Product: FC(F)Oc1cccnc1C1CC1
Temperature: 95 °C
Yield: 58 %

Procedure:
Prepared according to Preparation 48 using 3-difluoromethoxy-2-bromopyridine (Preparation 217) and cyclopropylboronic acid. The reaction was heated to 95° C. for 18 hours before cooling to room temperature and filtering through arbocel. The filtrate was concentrated in vacuo and purified using silica gel column chromatography eluting with ethylacetate:heptane 1:5 to furnish the title compound as a colourless oil (273 mg, 58%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](=[O:21])=[O:20].Cl>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][N:10]=1)[C:19]([OH:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1ccc(OCc2ccccc2)nc1
Reactant: O=C=O
Agent: Cl
Solvent: C1CCOC1
Product: COCOc1cnc(OCc2ccccc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(benzyloxy)-5-(methoxymethoxy)pyridine (8.00 g) in THF (50 mL) was added 1.6 M n-butyllithium-hexane solution (30.6 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hr. To the reaction mixture was added an excess amount of dry ice, and the mixture was allowed to warm to room temperature. 1 M Hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (9.30 g).
Reaction SMILES: N[C:2]1C(N)=C(C)C=CC=1.NC(N)=O.[C:14](=[O:28])([O:16][C:17]1[CH:23]=[C:22]([O:24][C:25](=[O:27])[NH2:26])[CH:21]=[CH:20][C:18]=1C)[NH2:15]>>[C:25](=[O:27])([O:24][C:22]1[CH:21]=[CH:20][CH:18]=[C:17]([O:16][C:14](=[O:28])[NH2:15])[C:23]=1[CH3:2])[NH2:26]
Reactant: Cc1cccc(N)c1N
Reactant: Cc1ccc(OC(N)=O)cc1OC(N)=O
Agent: NC(N)=O
Product: Cc1c(OC(N)=O)cccc1OC(N)=O

Procedure:
Then, this reaction may be carried out, for example, by charging the mixed diaminotoluene, urea and/or N-unsubstituted carbamic acid ester, alcohol, if necessary, a catalyst and a reaction solvent, in a reaction vessel under the above-described conditions, and stirring or mixing the charged mixture. Tolylene dicarbamate containing 2,4-tolylene dicarbamate and 2,6-tolylene dicarbamate is produced as a main product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]2)=[O:19])[C:13](OC)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:37][C@H:38]([C:51](=[O:64])[N:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=2)[CH2:54][CH2:53]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25]2)=[O:19])[C:13]([NH:37][C@H:38]([C:51](=[O:64])[N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:59]=[CH:60][N:61]=[CH:62][CH:63]=3)[CH2:54][CH2:53]2)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCN(c2ccncc2)CC1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate (95 mg, 0.2 mmol) in DMF (2.0 mL) was added (S)-tert-butyl 5-amino-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate (78 mg, 0.2 mmol) followed by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol) and triethylamine (1 mL). After stirring at room temperature for 2 h, the solvent was removed and the crude product was purified by flash chromatography using 7% methanol in dichloromethane containing 2% ammonium hydroxide (ammonia content 28-30%) to give tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate in 87% yield as white solid. 1H-NMR (CD3OD) δ 8.11-8.10 (m, 2H), 7.97 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.50-7.44 (m, 3H), 7.32-7.30 (d, J=7.5 Hz, 2H), 7.23-7.20 (m, 1H), 7.13 (s, 1H), 6.77 (d, J=6.5 Hz, 1H), 4.83-4.81 (m, 1H), 4.67-4.65 (m, 1H), 4.14-4.08 (m, 2H), 3.82-3.78 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m, 1H), 3.48-2.80 (m, 10H), 2.52 (s, 3H), 1.84-1.78 (m, 2H), 1.69-1.61 (m, 1H), 1.40 (s, 9H), 1.49-1.11 (m, 8H); MS (ESI) 847 (M+H) ; Rf=2.34.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C@@H:7]1([C:16](O)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13](O)=[O:14].CCOCC>O1CCCC1>[OH:14][CH2:13][C@@H:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]1[CH2:16][OH:17]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC[C@@H]1CCCC[C@H]1CO
Yield: 72.5 %

Procedure:
To a mixture of lithium aluminum hydride (52.22 g; 1.374 mol) and tetrahydrofuran (500 ml), a solution of trans-1,2-cyclohexanedicarboxylic acid (5) (118.18 g; 0.687 mol) in tetrahydrofuran (2 liters) is dropwise added under reflux, and the resultant mixture is allowed to react under reflux for 3 hours. After completion of the reaction, the reaction mixture is cooled, and wet tetrahydrofuran and ether are dropwise added thereto, followed by filtraion. The filtrate is concentrated under reduced pressure to give trans-1,2-bis(hydroxymethyl)cyclohexane (2) (71.86 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:16]([O-])=O)[CH:3]=1.C1COCC1>[Pt].CO>[Cl:1][C:2]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([CH:3]=1)[NH2:16]
Reactant: CNc1cc(N2CCOCC2)c(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCOCC2)c(Cl)cc1N

Procedure:
The sub-title compound was prepared from (4-chloro-5-morpholin-4-yl-2-nitro-N-methyl-aniline (260 mg, 1.0 mmol), THF (6 mL), MeOH (6 mL) and Pt/C (50 mg) in analogy to example 1 step (f).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cn2c(N)cc(=O)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt, [M−3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (17.0 g, 69.0 mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH2:4]=[O:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl>CC#N>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][C:10]=1[CH:4]=[O:5]
Reactant: C=O
Reactant: COc1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: COc1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of MgCl2 (3.48 g, 37.0 mmol), TEA (12.8 mL, 92.1 mmol) and paraformaldehyde (5 g, 167 mmol) in MeCN (100 mL) was added 4-methoxy-phenol (3 g, 24.2 mmol). The mixture was refluxed for 8 hours, cooled to room temperature, then poured into 5% HCl (300 mL), extracted with ethyl acetate (200 mL×3). The combined organic layer was dried, concentrated and purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/5) to give 2.3 g of 2-hydroxy-5-methoxy-benzaldehyde (4A).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][O:11][C:10]([CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:12]
Reactant: CC(C)(CO)CBr
Reactant: CCCC1CCC(C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCC1CCC(C(=O)OCC(C)(C)CBr)CC1
Temperature: 25 °C

Procedure:
4-Propyl-cyclohexanecarboxylic acid (10.0 g, 58.0 mmol), 3-bromo-2,2-dimethyl-propan-1-ol (10.0 g, 59.9 mmol) and a catalytic amount of para-toluene sulphonic acid are stirred under reflux in toluene (300 ml) in a flask equipped with Dean-Stark apparatus over night. The solution is allowed to cool to room temperature, is washed with aqueous sodium carbonate and water, dried and evaporated to dryness. Purification is achieved by filtration through a silica pad using petrol as eluant. Evaporation of the appropriate fractions gives 4-propyl-cyclohexanecarboxylic acid 3-bromo-2,2-dimethyl-propyl ester as a liquid. The structure is confirmed by GCMS.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[C:13]([O:17][C:18](=[O:37])[NH:19][C@H:20]([CH2:35]O)[CH2:21][C:22]([CH3:34])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:16])([CH3:15])[CH3:14].[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18](=[O:37])[NH:19][C@H:20]([CH2:35][N:42]1[C:38](=[O:48])[C:39]2[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:41]1=[O:43])[CH2:21][C:22]([CH3:34])([CH3:33])[CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(CCOCc1ccccc1)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(CCOCc1ccccc1)C[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
DEAD (4.49 ml, 28 mmol) is added to a stirred suspension of ((S)-5-benzyloxy-1-hydroxymethyl-3,-3-dimethyl-pentyl)-carbamic acid tert-butyl ester (prepared as described in EP 0702004 A2, Rueger et al., 10 g, 0.028 mmol), phthalimide (4.19 g, 0.028 mmol) and PS-triphenylphosphine (29.8 g, 56 mmol) in THF (500 ml), and the resulting reaction is stirred at room temperature for 3 days. The reaction is filtered to remove the PS-triphenylphosphine resin and the resin is washed with EtOAc (2×50 ml). The solvent is removed in vacuo and the residue is purified by flash chromatography (SiO2, EtOAc/iso-hexane) to afford [(S)-5-benzyloxy-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3,3-dimethyl-pentyl]-carbamic acid tert-butyl ester as a white solid; [M+H]+ 481.
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].P(Br)(Br)[Br:18]>C(OCC)C>[CH2:2]([Br:18])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr
Yield: 216.5 %

Procedure:
A solution of 2.00 g (9.0 mmol) of (E,E)-farnesol in 20 ml of dry diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 735 μl (4.0 mmol, 0.45 eq.) of PBr3 in 4 ml of dry diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with H2O and separated. The organic phase was washed with 15 ml of NaHCO3, 15 ml of H2O, and 15 ml of brine, dried over MgSO4 and evaporated to provide 2.47 g of crude farnesyl bromide as a clear oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][N:19]([C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)C(=O)C(F)(F)F)([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:18][NH:19][C@@H:26]2[CH2:28][C@H:27]2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(CN[C@@H]2C[C@H]2c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 55.6 %

Procedure:
To a solution of methyl 1-benzyl-4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (68 mg, 0.143 mmol) in methanol (2 mL) was added sodium hydroxide (1M, 1 mL, 6.00 mmol), and the mixture was stirred at room temperature for 30 h. The mixture was purified using reverse-phase HPLC under the acidic conditions. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 29 mg of product (HCl salt) as white solid. MS: (M+H)+=365.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.39 (m, 1H), 1.67 (br. s., 1H), 1.96-2.10 (m, 2H), 2.18-2.39 (m, 2H), 2.61-2.74 (m, 1H), 2.86-3.03 (m, 2H), 3.08-3.24 (m, 2H), 3.59 (br. s., 1H), 4.22-4.50 (m, 2H), 7.11-7.39 (m, 5H), 7.46 (br. s., 3H), 7.62 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 120 °C
Yield: 95 %

Procedure:
To a solution of 4-(trifluoromethyl)phenol (3 g, 18.51 mmol) and 4-fluorobenzaldehyde (2.3 g, 18.53 mmol) in DMF (20 mL), was added Cs2CO3 (7.24 g, 22.21 mmol). The mixture was heated with a microwave condition at 120° C. for 4 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4 and evaporated in vacuo to afford the title compound (4.68 g, 95% yield) as a brown oil. LCMS: rt=3.58 min, [M+H+]=267
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[C:26]2=[N:27][CH:28]=[C:29]([C:31](O)=[O:32])[CH:30]=[C:25]2[N:24]=[CH:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:31]([C:29]3[CH:30]=[C:25]4[N:24]=[CH:23][N:22]([CH3:21])[C:26]4=[N:27][CH:28]=3)=[O:32])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: Cn1cnc2cc(C(=O)O)cnc21
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: Cn1cnc2cc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cnc21

Procedure:
3-Methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 3-Methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid. MS calcd. for C24H19ClN5O2 [(M+H)+] 444.1, obsd. 444.0.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:31]([F:34])([F:33])[F:32])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH:10]=[C:6]4[S:5][C:4]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[N:8][C:7]4=[O:9])=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:23]=1)([CH3:29])[CH3:28]
Reactant: CN1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(C)(C)O)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-({1-[4-(1-Hydroxy-1-methylethyl)-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-(4-methylpiperazin-1-yl)-1,3-thiazol-4(5H)-one was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and 1-Methyl-piperazine following General Procedure C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:10][C:11]1[C:14](=O)[C:13](=[O:16])[C:12]=1[O:17]CCCC)[CH2:7][CH2:8][CH3:9]>>[CH2:6]([O:10][C:11]1[C:12](=[O:17])[C:13](=[O:16])[C:14]=1[NH:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:7][CH2:8][CH3:9]
Reactant: NCCCBr
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Yield: 84 %

Procedure:
The solution of bromopropylamine base, cooled to 0° C., was slowly added dropwise with vigorous stirring and cooling to maintain the temperature below to the methanolic solution of Step A containing 1,2-dibutoxy-1-cyclobutene-3,4-dione. The mixture was stirred at 20° C. for 2 hours, polish filtered through diatomaceous earth, washed with methanol (2×0.25L) and the filtrate was added over a period of 1 hour with vigorous stirring to water (31.1L). The mixture was stirred at 0° C. for 2 hours. The solid was collected by filtration, washed with water (3×2L) and dried to vacuo at 50° C. to give 2137 g (84% yield) of the title compound as an off-white solid; m.p.=69° C.