Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[F:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>>[F:8][C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:1][C@@H:2]3[CH2:6][CH2:5][NH:4][C:3]3=[O:7])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 4-(4-fluoro-phenoxy)-phenol provided the title compound. MS ESI+: m/z=288 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:8][CH2:9][NH2:10])[CH:4]=[C:5]([CH3:7])[N:6]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]=O>>[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH2:19][CH2:20][CH:21]1[NH:10][CH2:9][CH2:8][N:3]2[C:2]([CH3:1])=[N:6][C:5]([CH3:7])=[C:4]12
Reactant: Cc1cn(CCN)c(C)n1
Reactant: Cc1ccc(CCC=O)c(C)c1
Product: Cc1ccc(CCC2NCCn3c(C)nc(C)c32)c(C)c1

Procedure:
Prepared according to the previously described general procedure (GP11) by reaction of 2-(2,4-dimethyl-imidazol-1-yl)-ethylamine with 3-(2,4-dimethyl-phenyl)-propionaldehyde. LC-MS: tR=0.62 min.; [M+H]+=284 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:44]N>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH:43][NH2:44])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NN
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)NN)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
A portion of the crude intermediate of example 58 above, (50 mg, 0.06 mmol) was added to a solution of hydrazine in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 25 mg, 60% of the desired material.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH:36]4[O:40][CH2:39][CH2:38][O:37]4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)(=O)=O)=CC=1>C(O)C>[O:37]1[CH2:38][CH2:39][O:40][CH:36]1[CH2:35][CH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([C@H:25]2[CH2:26][CH2:27][C@H:22]([CH2:21][O:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)[CH2:23][CH2:24]2)[CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reactant: Oc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(OC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A solution of 0.33 g of potassium hydroxide in 7 ml of 95 percent ethanol is treated with 1.12 g of p-fluorophenol. Thereafter, the mixture is treated with a solution of 2.26 g of [trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methyl p-toluenesulfonate in 23 ml of ethanol and stirred at 80° C. (bath temperature) for 24 hours. Subsequently, the reaction mixture is partitioned in 1N hydrochloric acid and methylene chloride. The organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether gives 1-[[trans-4-(trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]methoxy]-4-fluorobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=[CH:5][CH:4]=1.[NH:44]1[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][N:8]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH2:21][N:44]4[CH2:48][CH2:47][C@@H:46]([CH2:49][OH:50])[CH2:45]4)[CH:19]=[N:18][C:17]=3[NH:24][C:25]3[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: OC[C@@H]1CCNC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CC[C@@H](CO)C4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (0.310 g, 0.537 mmol) and (R)-pyrrolidin-3-yl-methanol (0.163 mL, 1.610 mmol) in dichloromethane (0.035 mL, 0.537 mmol) and methanol (0.022 mL, 0.537 mmol) was treated with sodium triacetoxyborohydride (0.341 g, 1.610 mmol). The solution was stirred at room temperature overnight. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 5% to 10% 2 M NH3.MeOH in CH2Cl2 to give (R)-(1-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)pyrrolidin-3-yl)methanol (0.188 g, 0.284 mmol, 52.9% yield). m/z (ESI, +ve ion) 663.2 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.[CH2:12]([N:14](CC)CC)C.O>C(#N)C>[O:1]1[C:10]2[C:5](=[N:6][C:7]([C:12]#[N:14])=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cccc2c1OCCO2
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc2c(n1)OCCO2
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Under an argon atmosphere, 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine 5-oxide (102 mg, 666 μmol) was dissolved in actonitrile (700 μL), added triethylamine (202 mg, 2.00 mmol) and trimethylsilylnitrile (529 mg, 5.33 mmol) at room temperature, and the mixture was stirred at 100° C. overnight. Under ice-cold conditions, water was added, and the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol), and the title compound (105 mg (yield 97%)) was obtained as a brown solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].[Cl-].[Na+]>C1COCC1>[CH2:19]([O:21][CH2:22][C:23]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:24])[CH3:20]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCOCC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml of THF are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) of n-butyllithium (2.5 M/hexane) are added dropwise. 30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride are added at −78° C. The reaction medium is stirred for 24 hours and then poured into a saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated off. 30.6 g (56%) of the expected product are obtained in the form of an orange-colored oil after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:8]([NH2:11])[CH2:9][NH2:10]>CCOCC.C(O)(C)C>[CH2:1]([NH:5][C:6]([NH:10][CH2:9][CH2:8][NH2:11])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN=C=O
Reactant: NCCN
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCNC(=O)NCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
A solution of n-butylisocyanate (19.83 g, 0.2 m) in Et2O (50 ml) was added over 40 minutes to a vigorously stirred solution of ethylenediamine (48.08 g, 0.8 m) in isopropanol (1000 ml). After stirring at 25° C. for 3 hours, and standing for about 16 hours, the mixture was filtered and the filtrate evaporated to dryness under reduced pressure initially using water aspiration and finally high vacuum at 70° C. The residue was stirred for 1 hour in 12N HCl (20 ml) and H2O (200 ml), filtered and the filtrate rendered alkaline with 40% NaOH and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel and eluted with 20% MeOH-CHCl3 saturated with NH3 to give 83 (19.7 g, 59%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7](O)=O)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[C:24](=[O:37])[N:25]([CH2:34][CH2:35][CH3:36])[C:26](=[O:33])[N:27]([CH2:30][CH2:31][CH3:32])[C:28]=1[NH2:29]>C(Cl)Cl>[CH2:34]([N:25]1[C:24](=[O:37])[C:23]2[NH:22][C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[N:29][C:28]=2[N:27]([CH2:30][CH2:31][CH3:32])[C:26]1=[O:33])[CH2:35][CH3:36]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C3CCOCC3)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.2 %

Procedure:
3.2 g (0.025 mol) of tetrahydropyran-4-carboxylic acid, 4.0 g (0.025 mol) of carbonyldiimidazole and 85 ml of absolute methylene chloride are stirred for 30 minutes at ambient temperature. After the addition of 5.7 g (0.025 mol) of 5,6-diamino-1,3-dipropyluracil, the mixture is stirred for 4 hours at ambient temperature and then evaporated down in vacuo. The residue is combined with 130 ml of water and 11.6 g of calcium hydroxide, stirred for 30 minutes at 80° C. and, after cooling, acidified with conc. HCl whilst cooling with ice. The mixture is extracted with ethyl acetate and the organic phase is dried and evaporated. Chromatography of the crystalline residue on silica gel (CH2Cl2 /CH3OH 99:1) yields 1.7 g of the title compound in the form of white crystals (15% of theory), m.p. 171°-172° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]=1
Reactant: COc1ccccc1NC(=O)c1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1NC(=O)C1=CNCCC1
Yield: 60 %

Procedure:
Twenty-seven grams of N-nicotinoyl-2-methoxyaniline was dissolved in 800 ml of 10% hydrous ethanol. To the solution, 5 g of 10% palladium-on-carbon was added and the mixture was hydrogenated at 40° to 50° C. under atmospheric pressure. After 2 mols of hydrogen was introduced over a period of about 6 hours, the reaction was stopped and the catalyst was removed. The liquid reaction mixture was concentrated and the residual oil was purified with column chromatography on silica gel and recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-methoxyaniline having a melting point of 126°-128° C. Yield=60%
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH2:29].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[CH2:28][NH:29][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(F)ccc2[N+](=O)[O-])CC1
Reactant: NCc1cc(Cl)cc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NCc3cc(Cl)cc(Cl)c3)ccc2[N+](=O)[O-])CC1
Yield: 41 %

Procedure:
t-Butyl 4-(5-fluoro-2-nitrophenyl)piperazine-1-carboxylate (1.3 mmol), 3,5-dichlorobenzylamine (1.3 mmol), N,N-diisopropylethylamine (1.3 mmol) were stirred at 80° C. in dry acetonitrile (25 mL) for 72 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 25% ethyl acetate in hexanes to afford the title compound (41%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1H), 7.67 (d, 1H), 7.31 (s, 1H), 7.21 (s, 2H), 6.13 (dd, 1H), 5.70 (d, 1H), 4.42 (d, 2H), 3.54 (m, 4H), 3.38 (m, 4H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 481.37; Observed: 482.6 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH:23][CH2:24][CH2:25][C:26]#[N:27])=O)[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C[Si]([N:65]=[N+:66]=[N-:67])(C)C>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[N:23]([CH2:24][CH2:25][C:26]#[N:27])[N:67]=[N:66][N:65]=2)[CH:16]=1)[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(C(=O)NCCC#N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](C#N)COCc1cccc(-c2nnnn2CCC#N)c1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of (S)-2-t-butoxycarbonylamino-3-[3-(2-cyanoethylaminocarbonyl)-benzyloxy]-propionitrile (3.8 g, 10.2 mmol) and triphenylphosphine (6.7 g, 25.5 mmol) in acetonitrile (75 mL) at 0° C. is added diisopropyl azodicarboxylate (5.0 mL, 25.5 mmol) and trimethylsilyl azide (3.73 mL, 28.1 mmol) dropwise, simultaneously, via syringe. The solution is then stirred at room temp. for 0.5 h, and then heated to 30° C. overnight. After solvent evaporation, the residue is taken up in EtOAc (150 mL), and then poured onto an ice—sat'd NaHCO3 mixture (150 mL), and extracted. The organic phase is washed with brine (100 mL), dried (MgSO4), evaporated and chromatographed (silica, 65% EtOAc/hexane) to yield (S)-2-t-butoxycarbonylamino-3-{3-[1-(2-cyanoethyl)-5-tetrazolyl]-benzyloxy}-propionitrile, as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:16])[CH3:15])[CH2:10]1.[Br:17]Br>ClCCl>[Br:17][CH2:15][C:14]([C:11]1[CH2:10][CH:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:13][N:12]=1)=[O:16]
Reactant: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)C1=NOC(c2c(F)cccc2F)C1
Temperature: 33 °C
Reaction time: 0.17 h

Procedure:
To a 500-mL flask equipped with a mechanical stirrer, thermometer, addition funnel and scrubber were added 1-(4,5-dihydro-5-(2,6-difluorophenyl)-3-isoxazolyl)ethanone (i.e. the product of Step B) (60.0 g, 0.27 mmol) and dichloromethane (130 mL). The reaction mixture was heated at 33° C., and a solution of bromine (39.2 mL, 0.24 mol) in dichloromethane (100 mL) was added dropwise via the addition funnel. After about 5 mL of the bromine solution had been added, the addition was stopped and the reaction mixture was stirred at 33° C. for about 10 minutes, during which time the color of the reaction mixture changed from red to yellow. The reaction mixture was cooled to 5° C., and the remaining bromine solution was added dropwise over 90 minutes. After the addition was complete, the reaction mixture was washed with sodium bisulfite solution (3.5 g in 100 mL of water). The organic layer was concentrated under reduced pressure, hexanes were added, and the resulting solid precipitate was collected by filtration and washed with hexanes to provide the title compound as a brown solid (73 g), which was used without further purification
Reaction SMILES: O=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:10][C:11](=[O:14])[NH:12][NH2:13])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([NH:12]/[N:13]=[CH:4]/[C:3]([CH3:5])=[CH2:2])=[O:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C=C(C)C=O
Product: C=C(C)/C=N/NC(=O)OC(C)(C)C

Procedure:
B-23a is prepared analogously to B-19a starting from methacroleine (1.18 ml, 14.3 mmol) and tert-butylcarbazate (1.89 g, 14.3 mmol). Yield: 2.61 g.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:24]=1)#[N:2].[OH-:25].[K+]>C(O)C>[CH3:23][N:20]1[CH2:21][CH2:22][C:17](=[C:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]3[CH:24]=[C:3]([C:1]([NH2:2])=[O:25])[CH:4]=[CH:5][C:6]2=3)[CH2:18][CH2:19]1
Reactant: CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CN1CCC(=C2c3ccc(C(N)=O)cc3CCc3cccnc32)CC1
Yield: 66 %

Procedure:
Ethanol (150 ml) was added to 2 g of 8-cyano-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine so that the latter was dissolved in the former. An aqueous solution of 2.8 g of potassium hydroxide was added further, followed by reflux for 3.5 hours. After the reaction, the solvent was distilled off under reduced pressure and a brine was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol 25:1 and 10:1), 1.4 g of 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine-8-carboxamide were obtained (yield: 66%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:15]=1)[CH3:10].O>ClCCl>[Br:1][C:13]1[S:12][C:11]([CH2:9][CH3:10])=[N:15][C:14]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: CCc1nc(-c2ccc(F)cc2)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCc1nc(-c2ccc(F)cc2)c(Br)s1
Reaction time: 2 h

Procedure:
At room temperature, 1.72 g (9.64 mmol) of N-bromosuccinimide are added a little at a time to a solution of 2.00 g (9.64 mmol) of 2-ethyl-4-(4-fluorophenyl)-1,3-thiazole in 40 ml of dichloromethane. After 2 h, 50 ml of water are added to the reaction mixture, and the organic phase is separated off, washed with saturated NHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. This gives 2.47 g (85%) of the desired product; 1H-NMR(DMSO-d6) δ: 7.92 (m, 2H), 7.32 (m, 2H), 3.02 (q, 2H), 1.31 (t, 3H).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[C:7]([CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(O)=[O:8]>C(Cl)Cl>[Cl:4][C:7]([CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][CH2:22][CH3:23])[CH:16]=[C:15]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])=[O:8]
Reactant: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)O)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCn1cc(Cc2ccc(C(=O)OC)cc2OC)c2cc(CC(C)C(=O)Cl)ccc21

Procedure:
Oxalyl chloride (1.88 g) was added dropwise to a stirred solution of methyl 4-[5-(2-carboxypro- pyl)-1-propylindol-3-ylmethyl]-3-methoxybenzoate (4.2 g) (prepared as described in Example 67, part c) in methylene chloride (100 ml) under a nitrogen atmosphere. After 2 hr the solvent was evaporated, the residue dissolved in ethyl acetate (50 ml) and the solvent evaporated. The residue was dissolved in tetrahydrofuran (50 ml) and the solvent again evaporated, and the residue used directly in the next step without characterization.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C(O)CC.O>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:14]=[C:13]([C:15]([OH:24])([C:20]([F:21])([F:22])[F:23])[C:16]([F:17])([F:19])[F:18])[CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[CH:3]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)OC(C)(C)C)cc(C(O)(C(F)(F)F)C(F)(F)F)c2)cc1
Temperature: 85 °C

Procedure:
To a mixture of tert-butyl 3-bromo-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzoate (1.2 g, 2.8 mmol) from Example 2.11 step B, (4-methylphenyl)boronic acid (0.5 g, 3.7 mmol), Pd[P(Ph3)]4 (0.16 g, 0.14 mmol), and K2CO3 (1.2 g, 8.5 mmol) under N2 was added 28 mL of degassed n-Propanol/water (4:1). The reaction was heated to 85° C. overnight. The mixture was cooled to room temperature, filtered over celite and concentrated. The crude material was taken up in EtOAc and sat. NaHCO3. The organic layer was extracted (3×) and washed with brine. The final organic layer was dried over Na2SO4, filtered and concentrated to 1.0 g of crude material. Purification using automated flash chromatography (SiO2, 120 g, 0-5% MeOH/DCM) gave, upon concentration, title product.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[P:20](Cl)([Cl:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C(OCC)C>[P:20]([Cl:29])([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]
Reactant: O=C(NO)OCc1ccccc1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(NOP(=O)(Cl)Oc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A mixture of benzyl N-hydroxycarbamate (0.35 g, 2.1 mmol) and triethylamine (0.21 g, 2.1 mmol) in diethyl ether is cooled at 0° C. with stirring. To this is added a solution of phenyl dichlorophosphate (0.43 g, 2 mmol) in diethyl ether (1 ml). The resulting suspension is stirred at room temperature for 3 hours. It is then filtered and the solvents evaporated under reduced pressure to give 0.70 g of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][CH:39]([CH3:41])[CH3:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH2:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])[CH:39]([CH3:41])[CH3:40]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)CNS(=O)(=O)c1cccc(N)c1
Product: CC(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-isobutyl-benzenesulfonamide [CAS 608523-95-1] according to general procedure II. Yellow solid. MS (ISP) 584.1 [(M−H)−]; mp 205° C.