Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:21])[CH3:20])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:21][N:19]([CH3:20])[C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:22])=[CH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:66]([C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:56]=3)=[O:67])=[CH:14][CH:13]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Reaction time: 3 h

Procedure:
A solution containing methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was treated with 2-naphthoic acid (0.062 g, 0.36 mmol). The reaction mixture was stirred for 3 hours before diluting with water. The thus quenched reaction mixture was extracted with EtOAc and the combined organic extracts was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the crude product methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:20]([C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)(=[O:22])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: COc1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with naphthalene-2-sulfonyl chloride
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([N:37]=[N+:38]=[N-:39])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.16 g, 2.00 mmol) in 10 ml of DMF is added sodium azide (0.65 g, 10 mmol). The reaction mixture is stirred for 48 h at 50° C. The mixture is diluted with ethyl acetate, washed 3 times with water and 1 time with brine. The organic layer is dried with sodium sulfate, filtered and concentrated under reduce pressure to give 3-[(trans-4-azido-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]3)=[O:10])[CH2:4]1.[CH:26](CS([O-])(=O)=O)([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:22][C:20]([C:15]1[N:16]([CH:26]([CH3:28])[CH3:27])[C:17]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([N:2]([CH3:25])[CH3:1])[CH2:4]1)=[O:10])=[CH:19][CH:18]=2)=[O:21])[CH3:24]
Reactant: CC(C)CS(=O)(=O)[O-]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc2n1C(C)C

Procedure:
To a solution of ethyl 5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylate (1.51 g, 4 mmol) in acetonitrile (30 ml) were added isopropylmethane-sulfonate (1.8 eq, 1.1 g) and caesium carbonate (1.8 eq, 2.6 g). The mixture was heated overnight at reflux. The solvent was evaporated under reduced pressure and the residue partitioned between water and tert-butylmethyl ether. The phases were separated, the aqueous phase extracted with tert-butylmethyl ether and the combined organic phases washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (4:1 chloroform/methanol eluant) to afford the product as a light-brown gum. (31%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].Cl.Cl.[CH2:15]1[C@@H:20]2[CH2:21][NH:22][CH2:23][CH2:24][N:19]2[CH2:18][CH2:17][O:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:22]2[CH2:23][CH2:24][N:19]3[C@H:20]([CH2:15][O:16][CH2:17][CH2:18]3)[CH2:21]2)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: C1CN2CCOC[C@@H]2CN1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN3CCOC[C@@H]3C2)ccc1[N+](=O)[O-]
Yield: 75 %

Procedure:
5-Fluoro-2-nitrophenyl methyl ether (Example 22, step A) (0.318 g, 1.86 mmol), (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (Example 87, step G) (0.190 g, 0.880 mmol) and K2CO3 (0.614 g, 4.44 mmol) were stirred in DMSO (4 mL) at rt overnight. The reaction was diluted with EtOAc, washed with H2O (3×), dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step A (0.196 g, 0.660 mmol, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12-2.24 (m, 3H), 2.68 (d, J=11.4 Hz, 1H), 2.78-2.84 (m, 1H), 2.96 (td, J=12.3, 3.3 Hz, 1H), 3.10-3.18 (m, 1H), 3.52 (td, J=11.5, 2.4 Hz, 1H), 3.75 (dd, J=11.0, 2.9 Hz, 3H), 3.82-3.88 (m, 1H), 3.89 (s, 3H), 3.97 (d, J=13.9 Hz, 1H), 6.52 (d, J=2.6 Hz, 1H), 6.59 (dd, J=9.2, 2.6 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[CH2:24][C:23]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]([OH:33])[CH2:25]3)[O:22][N:21]=2)[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[CH2:24][C:23]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[CH2:25]3)[O:22][N:21]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OC1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of oxalyl chloride (64.6 μL, 0.74 mmol) in 5 mL of anhydrous CH2Cl2 was cooled to −60° C.; DMSO (105 μL, 1.48 mmol) was added dropwise so as to keep the reaction at the same temperature. After 15 min. the compound of Example 82 (174 mg, 0.49 mmol) dissolved in 1 mL of anhydrous CH2Cl2 was added and after 30 minutes TEA (0.413 mL, 2.96 mL) was added dropwise. Turning off the cooling and heating up to r.t., the reaction mixture was stirred for 3 hours, then it was quenched with H2O, extracted with CH2Cl2 and dried on Na2SO4. The residue from evaporation was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a brownish oil. Yield: 50%
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Cl[C:61]1[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][N:66]=1.CC1(C)C(C)(C)OB([C:77]2[CH:82]=[CH:81][C:80]([OH:83])=[CH:79][CH:78]=2)O1>>[OH:83][C:80]1[CH:81]=[CH:82][C:77]([C:61]2[C:62]([C:67]#[N:68])=[N:63][CH:64]=[CH:65][N:66]=2)=[CH:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: N#Cc1nccnc1Cl
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: N#Cc1nccnc1-c1ccc(O)cc1

Procedure:
Compound 86A was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with 3-chloropyrazine-2-carbonitrile and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 10.14 (s, 1H), 8.95 (d, J=2.45 Hz, 1H), 8.73 (d, J=2.45 Hz, 1H), 7.83-7.85 (m, 2H), 6.95-6.99 (m, 2H). ESI (+)/MS: 211 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.[Br:39]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:39][CH2:21][C:22]1[O:23][C:24](=[O:38])[C:25]2[C:30]([C:31]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: O=c1oc(CO)c(-c2ccccc2)c2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.6 %

Procedure:
Triphenylphosphine (250 mg, 0.953 mmol) was added to a solution of 3-(hydroxymethyl)-4-phenyl-1H-isochromen-1-one (intermediate B2, 185 mg, 0.733 mmol) and perbromomethane (316 mg, 0.953 mmol) in DCM (3.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 3 days, adding the reagents several times to achieve completion (overall 4 equivalents). The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 50 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (0.11 g, 47.6%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11](OCC)=[O:12])[N:10]=2)[CH:7]=1.O.[NH2:18][NH2:19]>CCO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:16])=[C:9]([C:11]([NH:18][NH2:19])=[O:12])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1nc2ccc(I)cn2c1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1c(C(=O)NN)nc2ccc(I)cn12
Temperature: 80 °C

Procedure:
To a stirred solution of ethyl 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (250 mg) in EtOH (5 ml) was added hydrazine hydrate (0.14 ml) at room temperature. The reaction vessel was sealed and heated at 80° C. for 16 h. The mixture was then cooled to room temperature, and the reaction mixture was concentrated in vacuo. The residue was washed with EtOAc to give the title compound (200 mg) as a light yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH:8]1[C:9]2[NH:1][C:2]3[C:3](=[CH:18][CH:19]=[CH:20][CH:16]=3)[C:4]=2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2[nH]c3ccccc3c12
Yield: 13.5 %

Procedure:
A mixture of 52.56 g of methyl indole-4-carboxylate, 51.55 g of 2,5-dimethoxytetrahydrofuran and 28.53 g of p-toluenesulfonic acid monohydrate in 300 ml of methanol was refluxed for 10 hours. Then, following a treatment similar to that of Example 1(1), there was obtained 9.14 g of methyl carbazole-4-carboxylate.
Reaction SMILES: FC1C(O)=C(F)C(F)=C(F)C=1F.[C:13]([O:17][C:18]([C@H:20]([C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([NH:33][NH2:34])=[O:32])[CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:39]([N:46]=[C:47]=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:13]([O:17][C:18]([C@H:20]([C@@H:30]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([NH:33][NH:34][C:47](=[O:48])[NH:46][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:32])[CH2:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C[C@@H](C(=O)NNC(=O)NCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.09 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide pentafluorophenol salt in 5 ml of pyridine was treated with 0.25 ml of benzyl isocyanate under a nitrogen atmosphere. The mixture was stirred for 2 hours at room temperature and then evaporated. The residue was dissolved in ethyl acetate and washed in sequence with 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulphate and evaporated to give a yellow oil. This was dissolved in ethyl acetate and washed twice with 0.5% aqueous sodium hydroxide and then with saturated aqueous sodium chloride. The organic layer was again dried over anhydrous magnesium sulphate and evaporated to give 0.946 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-(benzyl)carbamoyl-4-methylvalerohydrazide in the form of a pale yellow foam.
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:9]([O:11][C:12]([C@@H:14]1[CH2:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[C:16]([CH3:26])[C@H:15]1[OH:27])=[O:13])[CH3:10].N1C=CN=C1>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@H:14]1[CH2:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[C:16]([CH3:26])[C@H:15]1[O:27][Si:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:13])[CH3:10]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CC(c2ccc(C)cn2)=C(C)[C@H]1O[Si](CC)(CC)CC
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Triethylsilyl chloride (145 μL, 0.863 mmol, 1.5 equiv) was added dropwise to a solution of alcohol 88 (150 mg, 0.575 mmol) and imidazole (17 mg, 1.72 mmol, 3 equiv) in methylene chloride (4 ml) at 0° C. After stirring at 0° C. for 2 hr, the reaction was quenched with water (2.5 ml), and extracted with ethyl acetate (3×5 ml). The organic extracts were washed with brine (3.5 ml), and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvents in vacuo furnished an oily crude product which was purified by flash column chromatography on silica (2-7% EtOAc/hexanes-) to give 93 (198 mg, 92%) as a yellow oil: [α]22D=−51.04 (c=0.7, CHCl3); TLC Rf=0.29 (silica gel, 25% EtOAc/hexanes); 1H NMR (600 MHz, CDCl3) δ 8.41 (s, 1H), 7.45-7.42 (dd, 1H, 3J=1.8 Hz, 2J=8.4 Hz), 7.2-7.18 (d, 1H, 3J=7.8 Hz), 5.12 (d, 1H, 3J=4.8 Hz), 4.2-4.16 (dd, 2H, 3J=7.2 Hz, 2J=14.4 Hz), 3.17-3.12 (m, 1H), 3.0-2.89 (m, 2H), 2.3 (s, 3H), 1.97 (s, 3H), 1.29-1.26 (t, 3H, 3J=14.4 Hz), 0.98-0.95 (t, 9H, 3J=7.8 Hz), 0.67-0.63 (q, 6H, 3J=7.8 Hz); 13C NMR (100 MHz, CDCl3) δ 175.31, 153.31, 149.87, 139.09, 136.51, 134.07, 131.15, 122.39, 84.53, 60.83, 51.58, 37.40, 18.42, 14.46, 13.31, 7.03, 5.15; HRMS calcd for C21H33NO3Si+H+376.2308; found 376.2302 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15]C(C)([O-])C.[K+].IC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH3:15])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
1-tert-Butoxycarbonyl-3-oxopiperazine (see Tetrahedron Lett. (1980), 21(32), 3019-20 for outline of synthesis, 5 g) was dissolved in dry DMF (75 ml) and potassium tert-butoxide (3.08 g) was added. The mixture was stirred at ambient temperature for 1 hour, then iodomethane (3.9 g) was added, and stirring continued at the same temperature for 2.5 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100% ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 1-tert-butoxycarbonyl-4-methyl-3-oxopiperazine (3.92 g).
Reaction SMILES: [CH:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)=[CH2:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C:14]([OH:17])(=[S:16])[CH3:15]>C1C=CC=CC=1>[C-:3]1([CH2:1][CH2:2][O:17][C:14](=[S:16])[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: CC(O)=S
Reactant: C=C[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccccc1
Product: CC(=S)OCC[c-]1cccc1

Procedure:
In a typical experiment 2.12g (0.01 mol) of purified vinyl ferrocene and 0.76 (0.01 mol) of thioacetic acid were dissolved in 30 ml of GC spectrophotometric quality benzene and placed in a pyrex photoreactor fitted with a fritted purging tube and reflux condenser. The solution was purged 45 minutes with helium prior and during irradiation of 1.75×1019 photon/min. from a Hanovia 100 watt type SOL high pressure quartz mercury vapor lamp. No change in the infrared bands of the mercaptans (3.9μ) and vinyl groups (6.18μ) nor any product formation could be observed by thin layer chromatography during a photolysis time of up to eight hours. It was observed that photo-decomposition of vinyl ferrocene occurred (formation of dark brown precipitate) along with protection of thioacetic acid from the ultraviolet light.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].CN(/[CH:12]=[N:13]/[C:14]1[C:15]([C:26]([O:28]C)=O)=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=2)C.C(O)(=O)C>O1CCCC1>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][C:22]2[CH:23]=[C:14]3[C:15]([C:26](=[O:28])[C:7]([C:6]#[N:8])=[CH:12][NH:13]3)=[CH:16][C:17]=2[CH:18]=1
Reactant: COC(=O)c1cc2cc(OC)ccc2cc1/N=C/N(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2cc3[nH]cc(C#N)c(=O)c3cc2c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4.75 mL (11.88 mmol) of n-butyllithium (2.5M in hexane) in 4.0 mL of tetrahydrofuran at −78° C. is added dropwise a solution of 0.68 mL (13.1 mmol) of acetonitrile in 6.8 mL of tetrahydrofuran. After completion of addition, the suspension is stirred for 10 minutes. To this is added 1.36 g (4.75 mmol) of methyl 3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate in 32 mL of tetrahydrofuran dropwise. The resulting reaction mixture is stirred at −78° C. for 1 hour, at −5° C. for 1 hour and at room temperature for 15 minutes. The reaction mixture is again cooled to −78° C. and 1.72 g (28.6 mmol) of acetic acid is added dropwise. After addition of the acetic acid, the reaction mixture is allowed to warm to room temperature. The precipitate is collected by filtration and washed sequentially with water, acetonitrile and methanol. After drying in vacuo, this yields 796.9 mg (67%) of 7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile as a deep yellow solid, mp>260° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([OH:21])[C:12]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:28]1([S:38](Cl)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.N1C=CC=CC=1>ClCCl>[C:28]1([S:38]([O:21][C:13]2[C:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=2)(=[O:40])=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(O)c2-c2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(OS(=O)(=O)c3cccc4ccccc34)c2-c2ccccc2)cc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-2-(trifluoromethyl)pyrimidin-4-ol (0.1 g, 0.25 mmol, prepared according to the procedure described in PCT/IB03/01289) in dichloromethane (10 ml) was added naphthalene-1-sulfonyl chloride (0.086 g, 0.37 mmol) in dichloromethane (4 ml) at 0° C. and the mixture was stirred for 10 minutes. Subsequently pyridine (0.04 ml, 0.5 mmol) was added under stirring and the stirring was continued further for 6 hours at 37° C. Dichloromethane was removed under vacuo and the resultant mixture was diluted with water:ethyl acetate (1:1, 100 ml) and then extracted with ethyl acetate (25 ml×3). The organic layer was washed with brine (100 ml), dried over anhydrous sodium sulphate and evaporated to afford the title compound (0.096 g, yield 67%); m.p. 204-206° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[N:7]([N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][N:12]1[CH2:13][CH2:14][N:9]([N:7]=[O:8])[CH2:10][CH2:11]1
Reactant: CC(C)CCBr
Reactant: O=NN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCN1CCN(N=O)CC1

Procedure:
A mixture of 3-methyl-1-bromo-butane (3.94 g.), N-nitroso-piperazine (3 g.), anhydrous potassium carbonate (3.6 g.) and a small crystal of potassium iodide in dimethyl formamide was heated at 100° for 2 hours. Solvent was removed under reduced pressure and the residue dissolved in ether and water. The ether extract was separated, dried and evaporated to give an oil which was adsorbed on silica gel. Elution with ethyl acetate gave N-(3-methylbutyl)-N'-nitroso piperazine, further purified by dissolving in dilute acid, washing the acid extract with ether, basifying the acid extract and re-extracting with ether. The yield of colourless oil was 3 g (62%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33](=O)[CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COCCNCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide (200 mg, 0.38 mmol) in anhydrous THF (10 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 1 mL, 2 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and then the organic layer was separated and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (90:10 CH2Cl2/MeOH) to give 30 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 8.79 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 7.61 to 7.46 (m, 7H), 7.06 (d, J=6.6 Hz, 2H), 6.84 (d, J=4.5 Hz, 2H), 6.44 (s, 1H), 3.85 (s, 2H), 3.49 (t, J=5.7 Hz, 2H), 3.29 (s, 3H), 2.81 (t, J=5.7 Hz, 2H), 1.31 (s, 9H); MS LC-MS [M+H]+=515, RT=2.02 min.