Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[C:42]([CH3:48])=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[C:42]=2[CH3:48])=[O:19])[N:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3C)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3C)c2cc1OC
Yield: 63.3 %

Procedure:
The title compound was prepared from phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (100 mg, 0.30 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylaniline (94 mg, 0.30 mmol) using Example 115C to give 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-methylphenyl)urea (106 mg, 0.19 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.59-7.51 (m, 5H), 7.39 (br s, 2H), 7.24 (t, 1H), 6.96 (d, 1H), 6.39 (s, 1H), 4.02 (s, 6H), 1.96 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].Br[CH:7]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:8]>O>[OH:2][CH:7]([C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[CH3:8]
Reactant: CC(Br)c1cccc(C(=O)c2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CC(O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 120 °C

Procedure:
In an autoclave, 100 ml of water and 3.3 g of calcium carbonate and 10 g of 3-(1-bromoethyl)benzophenone were placed, and were then heated at 120° C. for 6 hours. The resultant reaction solution was extracted with benzene, and a formed benzene layer was then dried with anhydrous sodium sulfate, followed by distilling off the solvent. The resultant product had the spectrum data which were identical with those of 3-(1-hydroxyethyl)benzophenone.
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>CC(C)=O.O>[CH:17]1([CH2:16][N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]2)[CH2:19][CH2:18]1
Reactant: BrCC1CC1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cn(CC2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Powdered sodium hydroxide (10 g) was added cautiously to a stirred solution of indole-3-carboxylic acid (5 g) and (bromomethyl)cyclopropane (10 g) in dry acetone (50 ml). The mixture was stirred for 24 hours at room temperature then diluted with water (250 ml) and washed with dichloromethane (2×100 ml). The aqueous phase acidified to pH 2 and the precipitate isolated and dried (6.3 g), m.p. 157° C.; δH (360 MHz, CDCl3) 0.02-0.04 (2H, m, CH2), 0.18-0.28 (2H, m, CH2), 0.83-0.89 (1H, m, CH), 3.57 (2H, d, J=7 Hz, NCH2), 6.7-6.8 (2H, m, H-5, H-6), 6.9 (1H, d, J=7 Hz, H-7), 7.55 (1H, s, H-2), 7.72 (1H, d, J=7 Hz, H- 4); m/z 215 (M+, 100%), 174 (60), 144 (40).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][OH:21])[S:17][C:13]=2[N:12]2[C:22]([CH3:25])=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.[CH2:26]([O:28][C:29](=[O:39])[C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)=[O:31])[CH3:27].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:26]([O:28][C:29](=[O:39])[C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:21][CH2:20][C:19]#[C:18][C:16]2[S:17][C:13]3[N:12]4[C:22]([CH3:25])=[N:23][N:24]=[C:11]4[CH2:10][N:9]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:14]=3[CH:15]=2)=[CH:34][CH:33]=1)[CH3:27]
Reactant: Cc1nnc2n1-c1sc(C#CCO)cc1C(c1ccccc1Cl)=NC2
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1ccc(OCC#Cc2cc3c(s2)-n2c(C)nnc2CN=C3c2ccccc2Cl)cc1
Yield: 73 %

Procedure:
As in Example 15, 4-(-2-chlorophenyl)-2-(3-hydroxy-1-propynyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (0.369 g) was reacted with 4-hydroxyphenylglyoxylic acid ethyl ester (0.195 g) in the presence of diethyl azodicarboxylate (0.175 g) and triphenylphosphine (0.263 g) in dichloromethane (30 mL). The crude reaction product, isolated in the usual manner, was purified by flash chromatography over silica gel (120 g; ethanol-dichloromethane; 3.5:96.5) to furnish 0.398 g of 4-[3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl]-2-propynyloxy]-alpha-oxobenzeneacetic acid ethyl ester (4:1 ) hydrate as a white foam.
Reaction SMILES: [Na].[CH2:2]([C:9]#[N:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[C:3]1([C:2](=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]#[N:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N#CCc1ccccc1
Reactant: CCCCCC=O
Agent: [Na]
Solvent: CO
Product: CCCCCC=C(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
Sodium (27.6 g, 1.2 mol) is dissolved in methanol (550 ml) and benzyl cyanide (140.4 g, 1.2 mol) is added, followed by dropwise addition over 45 min. of hexanal (164.2 g, 1.44 mol), keeping the inside temperature between 20-25° C. The mixture is further stirred during 90 min. at room temperature, and then extracted 3 times with hexane. The organic layers are washed with water, 2 N aq. HCl-solution, then brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.04 mbar. The fraction distilling at 114-121° C. is collected (172 g) and subjected to a fine distillation over a Widmer-column to yield olfactorily pure 2-phenyl-oct-2-ene nitrile (113 g, 44%) as a colourless oil (b.p. 113-115° C./0.03 mbar).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:4][CH2:5][OH:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[S:17]([O:6][CH2:5][CH2:4][CH:3]([CH2:2][O:1][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])[CH2:7][CH2:8][CH2:9][O:10][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18])([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC(CO)CCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(CCOS(=O)(=O)c2ccc(C)cc2)COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution of 3-hydroxymethylhexane-1,6-diol (4 g, 0.027 mol) in pyridine (80 mL) stirred in an ice bath was added para-toluenesulphonyl chloride (16.9 g, 0.09 mol) in one portion. The mixture was allowed to warm to ambient temperature. After 48 hours the reaction was worked up using DCM (100 mL) which was washed with 1N HCl (2×100 mL). The organic layer was dried and concentrated to yield a very viscous, sticky oil which was analysed by NMR. This confirmed the desired material had been formed in a yield of 60% (9.9 g). The material was used without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH2:20]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([NH:12][CH2:13][CH2:14][CH2:15][N:16]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][CH2:18][CH2:19][NH:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: NCCCNCCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)NCCCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Yield: 58.8 %

Procedure:
To a stirred solution of p-toluenesulfonyl chloride (240 g, 1.26 mole) in pyridine (600 ml) at 0° C. was added a solution of 1,5,9-triazanonane (50.0 g, 0.381 mole) in pyridine (100 ml) under a dry nitrogen atmosphere, maintaining the temperature ≤60° C. The addition required 15 minutes. The solvent was removed in vacuo and the resulting yellow oil was dissolved in ethyl acetate (1 l) and H2O (500 ml). The ethyl acetate layer was separated, washed with 0.1N HCl, H2O and saturated NaCl solution and dried (MgSO4). The solution was decolorized with silica gel and the solvent was removed in vacuo to give 133 g (59% yield) of the crude product as a glassy solid: 1H NMR (CDCl3) δ 1.71 (quint, J=6.6 Hz, 4 H), 2.42 (s, 6 H), 2.43 (s, 3 H), 2.96 (quart, J=6.4 Hz, 4 H), 3.11 (t, J=6.8 Hz, 4 H), 5.12 (t, J=6.6 Hz, 2 H), 7.30 (m, 6 H), 7.63 (m, 2 H), 7.73 (m, 4 H).
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([C:13](O)=[O:14])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)([CH2:10][OH:11])[CH2:13][OH:14])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CC(CO)(CO)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 19 h

Procedure:
4.00 g (10.69 mmol) 2,2-bis(4-nitrobenzyl)malonic acid were dissolved in 40 ml tetrahydrofuran and added dropwise in a the course of 2 hours to 64.1 ml (64.1 mmol) of a borane-tetrahydrofuran complex 1.0 M solution in tetrahydro-furan. After 19 hours at 25° C., 50 ml water were carefully added. The reaction mixture was then partitioned between ethyl acetate and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue, 3.77 g (97%) of a white powder was used without further purification.
Reaction SMILES: [CH2:1]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:10]1[C:11](=[O:16])[CH2:12][CH:13]([NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCN1C(=O)C=CC1=O
Reactant: CCCCCCCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCCN1C(=O)CC(NCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-nonyl maleimide (0.01 M) prepared as described in Example 12 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[Br:7]/[C:8](=[CH:11]\N(C)C)/[CH:9]=O.C(O)C>C(O)(=O)C>[Br:7][C:8]1[CH:9]=[N:1][C:2]2[N:3]([N:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: CN(C)/C=C(\Br)C=O
Reactant: Nc1cc[nH]n1
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1cnc2ccnn2c1

Procedure:
3-Aminopyrazole (0.75 g, 9.04 mmol) was mixed with (2Z)-2-bromo-3-(dimethylamino)acrylaldehyde obtained at the previous step (1.85 g, 10.4 mmol). Absolute ethanol (20 mL) and glacial acetic acid (2 mL) were added. The reaction mixture was stirred under reflux for 16 h and evaporated to dryness. The residue was washed on a filter with cold ethanol/hexane mixture (3:1) and dried in a vacuum oven at 30° C. to give 6-bromopyrazolo[1,5-a]pyrimidine.
Reaction SMILES: C(OC([N:11]1[C:16](=[O:17])[CH2:15][CH2:14][C:13]([NH2:19])([CH3:18])[C:12]1=[O:20])=O)C1C=CC=CC=1.[ClH:21].[H][H].O>C(O)C.[Pd]>[ClH:21].[NH2:19][C:13]1([CH3:18])[CH2:14][CH2:15][C:16](=[O:17])[NH:11][C:12]1=[O:20]
Reactant: [H][H]
Reactant: CC1(N)CCC(=O)N(C(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1(N)CCC(=O)NC1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
N-Benzyloxycarbonyl-α-amino-α-methylglutarimide (2.3 g, 8.3 mmol) was dissolved in ethanol (200 mL) with gentle heat and the resulting solution allowed to cool to room temperature. To this solution was added 4N hydrochloric acid (3 mL) followed by 10% Pd/C (0.4 g). The mixture was hydrogenated in a Parr apparatus under 50 psi of hydrogen for 3 hours. To the mixture was added water (50 mL) to dissolve the product. This mixture was filtered through a Celite pad which was washed with water (50 mL). The filtrate was concentrated in vacuo to afford a solid residue. The solid was slurried in ethanol (20 mL) for 30 min. The slurry was filtered to afford 1.38 g (93%) of α-amino-α-methylglutarimide hydrochloride as a white solid: 1H NMR (DMSO-D6) δ 11.25 (s, 1H), 8.92 (s, 3H), 2.84-2.51 (m, 2H), 2.35-2.09 (m, 2H), 1.53 (s, 3H); HPLC, Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4(aq), 1.03 min (94.6%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[C:8]([CH:14]2[CH2:16][CH2:15]2)[N:7]=1>C(OCC)C>[Cl:5][C:6]1[N:7]=[C:8]([CH:14]2[CH2:15][CH2:16]2)[N:9]=[C:10]([NH:4][CH:1]2[CH2:3][CH2:2]2)[C:11]=1[F:12]
Reactant: NC1CC1
Reactant: Fc1c(Cl)nc(C2CC2)nc1Cl
Solvent: CCOCC
Product: Fc1c(Cl)nc(C2CC2)nc1NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Cyclopropylamine (11.4 g, 0.200 mol) is added to 4,6-dichloro-2-cyclopropyl-5-fluoropyrimidine 18 (4.80 g, 23 mmol) and the solution is stirred at room temperature for 1 h. The mixture is diluted with diethylether, washed two times with a saturated sodium bicarbonate solution. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to afford 6-chloro-N,2-dicyclopropyl-5-fluoro-4-pyrimidinamine 31 as a yellow oil (4.99 g, 95%) which is used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O)(=[O:3])[CH3:2].C1(P(=[CH:38][C:39]([O:41][CH3:42])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:42][O:41][C:39](=[O:40])/[CH:38]=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:12]=1
Reactant: CC(=O)OCCCCCOc1cccc(C=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)/C=C/c1cccc(OCCCCCOC(C)=O)c1
Yield: 80 %

Procedure:
Using the procedure of example 28, the title compound was prepared in 80% yield, from 2.6 g (10.4 mmol) of 3-[[5-(acetyloxy)pentyl]oxy]benzaldehyde and 4.0 g (12 mmol) of methyl (triphenylphosphoranylidene)acetate, as a colorless solid, mp 65°-67° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13]
Reactant: OCCCCCCCCCCCBr
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCCCCCCCCBr
Reaction time: 2 h

Procedure:
1-Bromo-11-hydroxyundecane (5 g, 20 mmoles) dissolved in methylene chloride (30 ml) was added to a suspension of pyridinium chlorochromate (6.4 g, 30 mmoles) in methylene chloride (25 ml) and stirred for 2 hours. The mixture was diluted with ether, filtered and concentrated in vacuo to afford 1-bromo-11-oxoundecane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:12]4[CH2:13][C:14]5[S:15][CH:16]=[CH:17][C:18]=5[C:11]=4[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH3:26])[N:9]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of the corresponding intermediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pental ene (1.34 g, 3 mmol), 4-Trifluoromethylphenylboronic acid (0.85 g, 4.5 mmol), Na2CO3 (2 M, 7 mL), and Pd(PPh3)2Cl2 (270 mg, 0.2 mmol) in toluene/ethanol (1:1, 18 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4′-Trifluoromethyl-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 35% yield.
Reaction SMILES: N1C=CC=CC=1.[OH:7][CH2:8][C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH:8]([C:9]1[CH:14]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[N:13]2[C:31](=[O:42])[C@@H:32]([NH:33][C:34](=[O:41])[CH2:35][C:36]3[S:37][CH:38]=[CH:39][CH:40]=3)[C@H:12]2[S:11][CH:10]=1)=[O:7]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)=CS[C@H]12
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
In this preparation 31 g. of dried chromium trioxide is added to a mixture of 51 g. of dry pyridine and 800 ml. of dry methylene chloride and stirred at 15°C under nitrogen for 20 minutes. 26 Grams of benzhydryl 3-hydroxymethyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4carboxylate in 250 ml. of dry methylene chloride is added in one portion. The resulting mixture is stirred for 30 minutes and then filtered through diatomaceous earth. The contents of the reaction flask and the diatomaceous earth are washed with 500 ml. of methylene chloride and combined with the preceding filtrate and then washed with 400 ml. of 5% aqueous potassium hydroxide solution, 500 ml. of 20% aqueous hydrochloric acid and twice with 400 ml. brine. The aqueous washings are back extracted with 500 ml. of methylene chloride and the extracts added to the previously washed methylene chloride filtrate, then dried over sodium sulfate and then stirred for one hour with 30 g. of silica gel. The mixture is filtered and the silica gel washed with 400 ml. 1:1 vol. ethyl acetate/methylene chloride. The combined filtrates are evaporated to dryness under reduced pressure and the resulting residue (26 g.) is recrystallized from ethyl ether/methylene chloride affording 21.4 g. of benzhydryl 3-formyl-7β-(thiophen-2-yl-acetamido)-ceph-2-em-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=O)[CH2:11]3)[N:7]([CH3:16])[C:6]=2[CH:17]=1.Cl.[NH2:19][OH:20]>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]3[CH2:13][CH:12]([CH:14]=[N:19][OH:20])[CH2:11]3)[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: NO
Reactant: Cn1c(C2CC(C=O)C2)nc2ccc(Br)cc21
Agent: Cl
Solvent: CCO
Product: Cn1c(C2CC(C=NO)C2)nc2ccc(Br)cc21

Procedure:
To a stirred solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanecarbaldehyde (less polar isomer, 200 mg) in EtOH (10 ml) was added hydroxylamine hydrochloride (50 mg), and the resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated in vacuo to afford the title compound (200 mg) as an off-white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C@@H:6]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH2:7][NH:8][CH3:9].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][N:8]([CH2:7][C@H:6]([O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:24]([CH3:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2)[CH3:5])[C:1](=[O:3])[CH3:2]
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Acetyl chloride (24 μl, 0.33 mmol) was added drop wise to a solution of 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (129 mg, 0.30 mmol, obtained as described in Example 103, preparation of starting materials) and DIPEA (105 μl, 0.6 mmol) in DCM (5 ml). The mixture was stirred at room temperature for 2 hours and diluted with DCM. The solution was washed with water and brine, and dried over MgSO4. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 2 to 4% methanol in DCM) to give the title compound (84 mg, 60%) as a pale solid; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.08 (s, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 3.08 (s, 3H), 3.56 (dd, 1H), 3.93 (dd, 1H), 5.09 (m, 1H), 6.92 (d, 1H), 7.12 (m, 3H), 7.50 (m, 2H), 7.65 (m, 1H), 7.70 (s, 1H), 8.27 (s, 1H), 8.62 (s, 1H); Mass spectrum: MH+ 472.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:16])=[C:11]([CH:15]=2)[C:12]([NH2:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:17]1[CH:22]=[C:21]2[C:23]([CH:26]=O)=[CH:24][S:25][C:20]2=[CH:19][CH:18]=1>>[N:1]1([C:7]2[CH:15]=[C:11]3[C:10](=[CH:9][CH:8]=2)[N:16]=[C:26]([C:23]2[C:21]4[CH:22]=[CH:17][CH:18]=[CH:19][C:20]=4[S:25][CH:24]=2)[NH:14][C:12]3=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1N
Reactant: O=Cc1csc2ccccc12
Product: O=c1[nH]c(-c2csc3ccccc23)nc2ccc(N3CCCCC3)cc12

Procedure:
Compound 28 was synthesized from 5-piperidinyl-2-aminobenzamide (12) (1.6 g, 7.3 mmol) and thianaphthene-3-carboxaldehyde (16) (1.2 g, 7.3 mmol): yield 1.6 g (60%); pale yellow crystals; mp>300° C.; 1H NMR (DMSO-d6) δ 1.57-1.59 (6H, m, (CH2)2CH2NCH2CH2), 3.22-3.25 (4H, m, CH2NCH2), 7.42-7.54 (4H, m, 4×ArH), 7.63-7.67 (1H, m, 1×ArH), 8.03-8.07 (1H, m, 1×ArH), 8.66 (1H, s, 1×ArH), 8.97-9.00 (1H, m, 1×ArH), 12.30 (1H, br s, NH) ppm; MS (ESI) m/z 361; Anal. (C21H19N3OS): C, H, N.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11](O)=[O:12]>C1C=CC=CC=1>[F:5][CH:6]([F:20])[O:7][C:8]1[C:9]([F:19])=[C:10]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[C:11]([Cl:3])=[O:12]
Reactant: O=C(O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
15 ml of thionyl chloride were added to a solution of 5.22 g (0.0216 moles) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid [(XII), R1 =--OCHF2, R3' =H, X=X'=F] (prepared as described in Preparation 1, 2 or 3) in 300 ml of benzene, and the mixture was heated under reflux for 3 hours. At the end of this time, benzene and excess thionyl chloride were removed by distillation under reduced pressure, to give 3-difluoromethoxy-2,4,5-trifluorobenzoyl chloride [(XIII), R1 =--OCHF2, R3' =H, X=X'=F].