Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1>>[C:19]([C:18]1[CH:22]=[CH:23][C:15]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][CH:17]=1)(=[O:20])[NH2:21]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(C(N)=O)cc1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluorobenzamide instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[F-:17]>CC(C)=O>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][S:12]([F:17])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)CCCCOc1ccccc1
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=S(=O)(F)CCCCOc1ccccc1
Yield: 90.9 %

Procedure:
4-Phenoxybutylsulfonyl fluoride (17) was synthesized as in 13.1 using 16 (0.4 g, 1.6 mmol) and NH4F (0.118 g, 3.2 mmol) in dry acetone (20 mL). Purification by flash column chromatography on silica gel gave 17 (0.338 g, 91% yield) as a white solid (m p 74-76° C.) 1H NMR (500 MHz, CDCl3) δ 7.29 (t, J=7.5 Hz, 2H), 6.97 (t, J=7.5 Hz, 1H), 6.89 (d, J=7.5 Hz, 2H), 4.03 (t, J=5.5 Hz, 2H), 3.52-3.48 (m, 2H), 2.20 (quintet, J=7.7 Hz, 2H), 2.00 (quintet, J=8.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=C[CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].ClC1N=C(Cl)C(C)=C[N:14]=1.Cl>CN(C=O)C.O>[N:11]1[CH:10]=[CH:9][C:4]([CH2:5][C:6]#[N:14])=[N:3][CH:8]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: N#CCc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccncn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.3 g, of NaH in a 60% dispersion oil, 32.5 mmol, 4 eq) in anhydrous DMF (10 mL), was added dropwise at room temperature a solution of 2-pyridylacetonitrile (960 mg, 8.12 mmol, 1 eq) in anhydrous DMF (10 mL). The reaction mixture was stirred at room temperature for 1 hour. A solution of 2,4-dichloro-5-methyl-pyrimidine (1.32 g, 8.12 mmo, 1 eq), dissolved in anhydrous DMF (5 ml), was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 14 hours. The mixture is hydrolysed with water (1 mL) and acidified with 1.6 mL of 10M HCl. The solvents were evaporated under vacuum. The residue was extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography with 50:50 (EtOAc:cHex). The fractions evaporated to give a yellow solid which was dried under vacuum at 40 degrees. The yellow crystalline product 4-pyrimidineacetonitrile, 2-chloro-5-methyl-alpha-2(1H)-pyridinylidene was isolated. (1.7 g, 86%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>ClCCl>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[S:6][C:5]3=[N:7][CH:8]=[CH:9][N:4]3[N:3]=2)=[CH:13][CH:12]=1
Reactant: Brc1nn2ccnc2s1
Reactant: Nc1ccc(F)cc1
Solvent: ClCCl
Product: Fc1ccc(Nc2nn3ccnc3s2)cc1
Temperature: 135 °C
Yield: 10.2 %

Procedure:
A mixture of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole (1.0 g, 4.90 mmol) and 4-fluoroaniline (1.86 mL, 19.60 mmol) was heated under microwave irradiation at 135° C. for 15 minutes. On cooling, the mixture was diluted with dichloromethane (10 mL) and purified by column chromatography (Biotage™/Flash, silica, methanol:dichloromethane 0.2:9.8 to 1:9). The residue obtained was treated with dichloromethane (5 mL) and filtered to give (4-fluoro-phenyl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl-amine as a beige solid (117 mg, 10% yield).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19](=[O:36])[CH2:20][NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][N:23]=[C:22]2[NH:21][CH2:20][C:19]([NH:18][CH:16]1[CH2:17][N:14]([CH:2]2[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]2)[CH2:15]1)=[O:36]
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)CC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)CC1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of ethyl 2-(4-oxocyclohexyl)acetate with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:17]Br>O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:9])[C:6]([Br:17])=[CH:7][CH:8]=1
Reactant: COc1cccc(C)n1
Reactant: BrBr
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(Br)c(C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
A mixture of 2-methoxy-6-methylpyridine (17.0 g, 138 mmol) and a solution of disodium hydrogen phosphate (0.15M in water, 250 mL) was stirred at room temperature. Bromine (7.1 mL, 138 mmol) was added dropwise over 15 min via an addition funnel. The reaction mixture was then stirred at room temperature for 4 h. The clear colorless solution was diluted with water (500 mL) and extracted with dichloromethane (200 mL) three times. The combined organic layers were dried over MgSO4, filtered and solvent was removed in vacuo from the filtrate to give a yellow liquid. Flash chromatography on silica gel (EtOAc:hexane::1:20) and removal of solvent from the desired combined fractions afforded a clear colorless liquid (15.4 g): 1H-NMR(CDCl3, 300 MHz): δ 7.60(d, 1H, J=8), 6.46 (d, 1H, J=8), 3.89 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[N:14][CH:13]=[CH:12][N:11]3[C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[N:14][CH:13]=[CH:12][N:11]3[C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: CC(C)Oc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Solvent: CC#N
Product: CC(C)Oc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A suspension of 2-(4-fluorophenyl)-8-isopropoxy-3-(2-methanesulfonylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (0.16 g, 0.37 mmol) and 3-amino-2,2-dimethylpropan-1-ol (TCI-US, 0.208 g, 0.74 mmol) in ACN (5 mL) was heated at about 80° C. overnight to give a clear solution. The reaction mixture was cooled to ambient temperature, the volatiles were evaporated, and the resulting residue was dissolved in DCM and washed with water. The organic phase was dried over MgSO4, filtered, and evaporated to give a white solid that was triturated with heptane to afford 0.109 g (64.7%) the title compound as a white solid: LC/MS (Table 1, Method g) Rt=3.01 min; MS m/z: 494.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])[NH:5][C:4](=[O:17])[CH:3]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C>[N+:18]([C:3]1[C:4](=[O:17])[NH:5][C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[F:16])=[CH:7][C:2]=1[OH:1])([O-:20])=[O:19]
Reactant: COc1ccc(F)c(-c2cc(O)cc(=O)[nH]2)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(F)c(-c2cc(O)c([N+](=O)[O-])c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
A suspension of 4-hydroxy-6-(2-fluoro-5-methoxyphenyl) pyridone (345 mg, 1.47 mmol) in acetic acid (5 mL) was treated dropwise with 90% nitric acid (0.8 mL) at room temperature. The resulting homogeneous solution was heated to 55°-60° C. for 5 h during which time a precipitate formed. After cooling to room temperature the yellow solid was collected by filtration, washed thoroughly with water, and dried under vacuum to give pure 3-nitro4-hydroxy-6-(2-fluoro-5-methoxyphenyl) pyridone.
Reaction SMILES: O.NN.[F:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH2:18][O:19][N:20]4C(=O)C5=CC=CC=C5C4=O)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:9]=2[CH:37]=1>C(O)C>[NH2:20][O:19][CH2:18][C:15]1[N:14]2[C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:37][C:9]=3[C:10]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:11][CH2:12][C:13]2=[N:17][N:16]=1
Reactant: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2
Agent: NN
Solvent: O
Solvent: CCO
Product: NOCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 2, a solution of hydrazine hydrate in ethanol is reacted at 65° C. with 8-fluoro-1-[(phthalimidooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 1-[(aminooxy)methyl]-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH:22]=[CH:21][CH2:20]1)[N:13]=2)[CH:5]=O.Cl.[NH:31]1[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][N:31]2[CH2:34][CH:33]([C:35]([O:37][CH3:38])=[O:36])[CH2:32]2)[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH:21]=[CH:22][CH2:23]1)[N:13]=2
Reactant: COC(=O)C1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC=CC4)nc3s2)c(F)c1
Agent: Cl
Product: COC(=O)C1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC=CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.48 g, 1.2 mmol), methyl azetidine-3-carboxylate hydrochloride (0.365 g, 2.41 mmol) according to Reference R and the general procedure for reductive amination gave methyl 1-((3-fluoro-4-(5-(1-phenylcyclopent-3-enyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-methyl)azetidine-3-carboxylate as an oil which partially solidified to a white solid. MS (ESI) m/z: Calculated: 499.0; Observed: 500.1 (M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:38]=[CH:37][C:8]([CH2:9][N:10]2[C:22]3[C:21]4[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:20]=4[CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:15]=3)=[CH:7][CH:6]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN(C=O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[C:22]3[N:10]([CH2:9][C:8]4[CH:37]=[CH:38][C:5]([O:4][CH2:3][CH2:2][N:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)=[CH:6][CH:7]=4)[C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:20]=2[CH:26]=1)=[CH:15][C:14]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:13][CH:12]=4
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)CCc1c-2n(Cc2ccc(OCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12
Temperature: 65 °C

Procedure:
Intermediate #18, 11-[4-(2-Chloroethoxy)-benzyl]-8-benzyloxy-3-methoxy-5,11-dihydro-6H-benzo[a]carbazole, (6 g, 11.5 mmol) in DMF was treated with KI (2.5 g, 15.0 mmol) and piperidine (12 mL) and heated to 65° C. for 18 hours. The reaction was worked up by pouring the crude reaction mixture into water and extracting with ethyl acetate. The ethyl acetate layer was washed with NaHCO3 aq., brine and dried over MgSO4. The resultant was chromatographed on silica gel using CH2Cl2 (100%), CH2Cl2 :MeOH (98:2), CH2Cl2 :MeOH (96:4) as the eluting solvents. The product (3.2 g) was isolated as an oil: 1H NMR (DMSO) 7.52-7.12 (m, 8 H), 6.98-6.82 (m, 5 H), 6.80 (dd, 1 H, J=8.4 Hz, 2.6 Hz), 6.73 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 5.56 (s, 2 H), 5.11 (s, 2 H), 3.98 (t, 2 H, J=6.0 Hz), 3.70 (s, 3 H), 2.85-2.78 (m, 2 H), 2.75 (s, 2 H), 2.60 (t, 2 H, J=6.5 Hz), 2.42-2.38 (m, 4 H), 1.70-1.58 (m, 4 H), 1.58-1.35 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]Br.[C:13]([Si:15]([CH3:18])([CH3:17])[CH3:16])#[CH:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:14]#[C:13][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: C#C[Si](C)(C)C
Product: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1

Procedure:
In any or all of the above embodiments, converting the 3,5-methoxybenzoic acid to the (E)-5-(2-halo-3-iodoallyl)-1,3-phenylene bis(2,2-dimethylpropanoate) may include (1) reducing the 3,5-methoxybenzoic acid to produce 3,5-dimethoxybenzyl alcohol, (2) brominating the 3,5-dimethoxybenzyl alcohol to produce 3,5-dimethoxybenzyl bromide, (3) reacting the 3,5-dimethoxybenzyl bromide with ethynyl trimethylsilane to produce (3-(3,5-dimethoxyphenyl)prop-1-ynyl)trimethylsilane, (4) desilylating the (3-(3,5-dimethoxyphenyl)prop-1-ynyl)trimethylsilane to produce 1,3-dimethoxy-5-(prop-2-ynyl)benzene, (5) adding protecting groups to the 1,3-dimethoxy-5-(prop-2-ynyl)benzene to produce 5-(prop-2-ynyl)-1,3-phenylene bis(2,2-dimethylpropanoate), wherein the protecting groups are pivaloyl groups added by reacting the 1,3-dimethoxy-5-(prop-2-ynyl)benzene with boron tribromide and then with pivaloyl chloride, and (6) halogenating the 5-(prop-2-ynyl)-1,3-phenylene bis(2,2-dimethylpropanoate) to produce (E)-5-(2-halo-3-iodoallyl)-1,3-phenylene bis(2,2-dimethylpropanoate), wherein the 2-halo corresponds to R4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:10])[CH3:9])=[N:6][CH:7]=1.[BrH:11].O.BrBr>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: Br
Reactant: CC(=O)c1ccc(Br)cn1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)cn1
Reaction time: 1 h

Procedure:
1-(5-bromopyridin-2-yl)ethanone (200 mg, 1.0 mmol) was dissolved in Acetic acid (50 mL) and HBr in Acetic acid (48% solution, 280 uL) was added along with water (100 uL). Warmed to 70 C and added Bromine (51.5 uL, 1.0 mmol) and stirred for 1 hour. The reaction was concentrated to give the desired product (280 mg) containing a small amount of dibrominated product. This material was used as is.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([C:19](=[O:43])[N:20]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)[CH:21]([C:23]1[NH:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[CH3:22])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].[OH:45]O.[OH-].[Na+]>CCO>[C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([C:19](=[O:43])[N:20]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[O:45])[NH2:42])[CH:36]=1)[CH:21]([C:23]1[NH:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[CH3:22])[CH2:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([OH:17])=[CH:14][C:15]=1[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(Cc1cccc(C#N)c1)C(C)c1nc(-c2ccccc2)c[nH]1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(Cc1cccc(C(N)=O)c1)C(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 7.5 °C
Reaction time: 18 h

Procedure:
A solution of [1-{(3-cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.070 g, 0.12 mmol) in 3 mL of EtOH was treated with 1.0 mL of 30% hydrogen peroxide followed immediately by 0.1 mL of a 6M aqueous solution of NaOH. The reaction mixture was stirred vigorously for 18 h and quenched by pouring into chilled (5-10° C.) water. The aqueous solution was extracted five times with Et2O and the combined extracts were dried over MgSO4, filtered, and concentrated to provide 0.051 g of [1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester as a colorless residue (HPLC: 84% @ 254 nm and 77% @ 214 nm). MS (ES+) (relative intensity): 612.5 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:8]([F:11])([F:10])[C:4]1[CH:3]=[C:2]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)c1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 1 a], 1-iodo-3-trifluoromethyl-benzene was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to give the title compound as brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][CH3:16])[CH2:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:17][C:18]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:19]=1[CH2:20][NH:21][C:22](=[O:33])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:15]([CH3:16])[C:22]([NH:21][CH2:20][C:19]1[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:18]=1[F:17])=[O:33])[CH2:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(NCc1cccc(F)c1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of (S)-5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentan-1-ol (109.2 mmol) in THF (200 mL) was added 4-nitrophenyl 2,3-difluorobenzylcarbamate (43.72 g, 142.0 mmol). The resulting solution was stirred at RT for 1 h. The solvent was removed and the resulting residue was dissolved in EtOAc (800 mL). The organic mixture was washed with NaOH (1 N, 100 mL×3), HCl (0.5 N, 100 mL), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAC and hexanes to give (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea (35.1 g, 76%) as a pale yellow oil. LRMS (M+H+) m/z 417.2.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][N:25]([CH3:36])[CH2:26][CH2:27][CH2:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[CH3:36][N:25]([CH3:24])[CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([NH:33]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:34][CH:35]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CN(C)CCCc1ccc(N)cc1
Product: CN(C)CCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone with 4-(3-dimethylaminopropyl)-aniline.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]4[O:22][CH2:23][O:24][C:17]=34)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:25][CH3:26].[I-].[Na+].[CH3:29][N:30]([CH:32]=O)C>C(#N)C>[N:30]1([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]5[O:22][CH2:23][O:24][C:17]=45)=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:25][CH3:26])[CH2:32][CH2:7][CH2:6][CH2:5][CH2:14][CH2:29]1
Reactant: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCBr
Reactant: CN(C)C=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(Nc3cccc4c3OCO4)ncnc2cc1OCCN1CCCCCC1
Temperature: 45 °C

Procedure:
A mixture of 7-(2-bromoethoxy)-4-(2,3-methylenedioxyanilino)-6-methoxyquinazoline (0.48 g) homopiperidine (0.322 ml), sodium iodide (0.002 g), DMF (5 ml) and acetonitrile (6 ml) was stirred and heated to 45° C. for 5 hours. The mixture was evaporated and the residue was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a 19:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. The material so obtained was triturated under diethyl ether to give the title compound as a solid (0.4 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.65 (m, 4H), 1.9 (m, 4H), 3.35 (m, 2H), 3.55 (m, 2H), 3.7 (m, 2H), 4.0 (s, 3H), 4.6 (m, 2H), 6.1 (s, 2H), 7.0 (m, 3H), 7.45 (s, 1H), 8.15 (s, 1H), 8.9 (s, 1H); Mass Spectrum: M+H+ 437.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:13]1([CH2:19][CH2:20][CH:21]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH3:12][O:11][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: O=CCCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](NCCCc2ccccc2)CC1

Procedure:
A solution of 2 g of methyl trans-4-aminocyclohexane-carboxylate-hydrochloride, 1.5 ml of 3-phenylpropionaldehyde and 1.3 g of sodium cyanoborohydride in 40 ml of dry methanol is stirred for 20 hours at ambient temperature. The mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate phases are dried, acidified with ethereal hydrochloric acid and the solvent is removed under reduced pressure. The residue is triturated with acetone, suction filtered and washed with acetone and then with ether. Yield: 1.9 g (59.1% of theory), Melting point: 258°-260° C.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[CH2:1]([S:8][CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=C(CBr)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CSCc1ccccc1)C1CC1
Reaction time: 48 h

Procedure:
Benzyl mercaptan (15.6 ml, 0.133 mol) was stirred in DCM (100 ml), triethylamine (20.5 ml, 0.146 mol) added, the mixture cooled in an ice/acetone bath and 2-bromo-1-cyclopropyl-ethanone, prepared as in WO 03/074495, (21.77 g, 0.133 mol) dissolved in DCM (100 ml) was added dropwise. The mixture was stirred for 48 h, washed with water, then brine, dried over sodium sulphate and evaporated.