Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]#[N:8])=[O:6])[CH3:3]>>[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C#N
Agent: Cl
Product: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1

Procedure:
Hydrogen chloride gas was bubbled through neat ethylcyanoformate (0.997 ml, 10.1 mmol) until the solution became a white solid, approximately 2 hours. The solid was partitioned between CH2Cl2 and water. The CH2Cl2 layer was collected dried (MgSO4) and concentrated to a white solid. The product was recrystallized from hot absolute ethanol to give the title compound (m. p. 169-170° C.). 1H NMR (CDCl3) δ 1.42 (t, 9H, 3× CH3), 4.50 (q, 6H, 3× CH2). 13C NMR (DMSO) δ 14.06 (CH3), 64.02 (CH2), 161.27 (CO), 166.86 (Triazine Ar).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([NH2:10])[C:8]#[N:9].C(N(CC)CC)C.[CH3:18][N:19]1[CH:23]=[C:22]([C:24](Cl)=[O:25])[C:21]([CH2:27][O:28][CH3:29])=[N:20]1.Cl.C(N(CC)CC)C>C(OCC)(=O)C.O>[CH3:18][N:19]1[CH:23]=[C:22]([C:24]([NH:10][CH:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)[C:8]#[N:9])=[O:25])[C:21]([CH2:27][O:28][CH3:29])=[N:20]1
Reactant: N#CC(N)c1ccco1
Reactant: COCc1nn(C)cc1C(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1nn(C)cc1C(=O)NC(C#N)c1ccco1
Yield: 77.8 %

Procedure:
In 100 ml of ethyl acetate was suspended 3.2 g of alpha-(2-furyl)-aminoacetonitrile hydrochloride, and with ice cooling, 4.5 g of triethylamine was added. Then, 3.8 g of 1-methyl-3-methoxymethylpyrazole-4-carboxylic acid chloride was gradually added at 0° to 5° C. with stirring. After the addition, the mixture was further stirred at room temperature for 2 hours. Water (50 ml) was added to dissolve the precipitated triethylamine hydrochloride. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column, and the column was eluted with hexane/ethyl acetate to give 4.3 g (yield 78.6%) of the desired alpha-(1-methyl-3-methoxymethylpyrazol-4-ylcarbonylamino)-(2-furyl)acetonitrile.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[OH2:17].[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:20]([O:21][C:22](=[O:17])[CH:18]=[C:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH3:19]
Reactant: O=C1c2ccccc2-c2ccccc21
Reactant: C1CCOC1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 75 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2 g (11.1 mmol, 1 eq) of 9-fluorenone in 15 mL of dry THF are dissolved in a flask equipped with a condenser, under Ar. 2.86 mL (14.43 mmol, 1.3 eq) of triethylphosphonoacetate are introduced and 577 mg (14.43 mmol, 1.3 eq) of 60% NaH in oil are added batchwise to the solution. The mixture is heated for 3 hours at 70-80° C. 1.10 mL (5.55 mmol, 1 eq) of triethylphosphonoacetate and 222 mg (5.55 mmol, 1 eq) of 60% NaH in oil are added to the medium. The mixture is stirred for 2 hours at 70-80° C. Water is added, then the THF is concentrated. The basic aqueous phase is extracted with AcOEt and the organic phase is washed with brine, dried over MgSO4, filtered and concentrated. The oil obtained is subjected to chromatography over silica gel (eluant: heptane/DCM: 1/0 to 0/1). A product in the form of yellow crystals is obtained (m=1.86 g, yield=67%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=[C:5](B(O)O)[CH:4]=[C:3]1[C:19]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]2[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=2[N:20]=1.[Cl:36][C:37]1[N:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[Cl:36][C:37]1[N:42]=[C:41]([C:5]2[CH:4]=[C:3]([C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)[C:2](=[O:1])[N:7]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:6]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[Si](C)(C)CCOCn1nc(B(O)O)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 97 °C
Reaction time: 3 h

Procedure:
1.32 g of 6-oxo-1-(2-trimethylsilanylethoxymethyl)-5-[1-(2-trimethylsilanylethoxy-methyl)-1H-benzimidazol-2-yl]-1,6-dihydropyridazine-3-boronic acid, 583 mg of 2,4-dichlorpyrimidine and 3,3 g of cesium carbonate are dissolved in 17 ml of a 1:4 mixture of water and dioxane, and argon is passed through the solution for degassing. After addition of 125 mg of (1,1′-bis(diphenyl-phosphine)ferrocene)palladium(II) chloride-dichloromethane complex, the solution is stirred at 97° C. for 3 hours. For workup, it is diluted with 50 ml of water and extracted several times with ethyl acetate. The combined organic phases are dried using a silica gel cartridge, and the solvent is distilled off. The crude product is purified by preparative RP-HPLC (0-100% acetonitrile in water (+0.01% trifluoroacetic acid)).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18].O>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 158.3 g (0.75 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 3 liters of dioxane, 730 ml (1.46 mol) of a 20% solution of phosgene in toluene was added dropwise within 45 minutes and the resulting mixture was then stirred for 2 hours at ambient temperature. 1.5 l of water were added, the mixture was stirred for a further 2 hours at ambient temperature and the precipitate formed was suction filtered. The product was washed thoroughly with water and dried in a circulating air dryer. Colourless crystals, m.p. 239°-240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:38](=[O:45])[CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42].O>C(Cl)Cl>[O:45]=[C:38]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:11]3=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:23]=[CH:24][N:10]3[N:9]=2)[CH:3]=1)[CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCC(=O)Nc1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
2-(5-Aminopyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.200 g, 0.508 mmol, synthesized as described in Example 3) was dissolved in DCM (10 mL) and pyridine (0.0820 mL, 1.02 mmol) was added, followed by the addition of methyl 4-chloro-4-oxobutanoate (77.0 mg, 0.508 mmol). The reaction mixture was stirred at room temperature for 30 min. Water (10 mL) was added to the reaction mixture followed by addition of CH2Cl2 (4×10 mL). The combined organic extracts were separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 4-oxo-4-((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)pyridin-3-yl)amino)butanoate (0.170 g, 65.9%). 60 mg of the residue was further purified by preparative HPLC (Condition B-89 as described in general methods) to obtain methyl 4-oxo-4-(5-(5-phenyl-4-(pyridin-2-ylmethylamino) pyrrolo[1,2-f][1,2,4]triazin-2-yl)pyridin-3-ylamino)butanoate. LCMS Condition B-79: retention time 1.88 min, [M+1]=508.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62-2.78 (m, 4H), 3.62 (s, 3H), 4.93 (s, 2H), 6.81 (d, J=2.4 Hz, 1H), 7.23-7.34 (m, 2H), 7.41-7.64 (m, 6H), 7.72-7.82 (m, 1H), 7.90-7.93 (m, 1H), 8.33-8.44 (m, 1H), 8.79-8.89 (m, 2H), 9.04-9.12 (m, 1H), 10.37 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.[OH2:23].N1[CH:29]=[CH:28]C=CC=1>C(OC(=O)C)(=O)C>[C:28]([NH:1][C@@H:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1)(=[O:23])[CH3:29]
Reactant: O
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 6α-amino androsta-1,4-diene-3,17-dione (1,4 g) in 5.5 ml of dry pyridine, 2.8 ml of acetic anhydride are added dropwise at room temperature. The solution is stirred for 90 minutes and then water is dropped into the cooled (0° C.) solution. After 10 minutes stirring the reaction mixture is extracted with five 100 ml portions of ethyl acetate which are collected and dried over anhydrous sodium sulphate. The solvent is then removed in vacuum to yield a crude which is purified by chromatography on silica gel so obtaining 1.30 g of pure 6α-acetylamino androsta-1,4-diene-3,17-dione;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.[CH3:20][CH:21]1[NH:26][CH2:25][C:24]2[S:27][C:28]([C:30]([O-])=[O:31])=[N:29][C:23]=2[CH2:22]1.[Li+]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:30]([C:28]3[S:27][C:24]4[CH2:25][NH:26][CH:21]([CH3:20])[CH2:22][C:23]=4[N:29]=3)=[O:31])[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4cc5cc(Cl)ccc5[nH]4)CC3)sc2CN1
Product: Cl

Procedure:
A reaction was effected in the same manner as in Example B-7 by using 1-[(5-chloroindol-2-yl)sulfonyl]piperazine and lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-carboxylate as starting materials, whereby the title compound was obtained as brown amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1([C@@:18]23[CH:25]=[CH:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1.O>C(Cl)Cl>[CH:15]1([C@@:18]23[C@H:25]([N:12]4[CH2:13][CH2:14][CH:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[O:2][CH3:1])[CH2:10][CH2:11]4)[CH2:24][C:23](=[O:26])[N:22]2[C@@H:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:20][O:19]3)[CH2:17][CH2:16]1
Reactant: COc1ccccc1C1CCNCC1
Reactant: O=C1C=C[C@@]2(C3CC3)OC[C@H](c3ccccc3)N12
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1C1CCN([C@@H]2CC(=O)N3[C@@H](c4ccccc4)CO[C@]23C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
To a mixture of 4-(2-methoxyphenyl)piperidine (0.951 g, 4.97 mmol) and (3S,7aR)-7a-cyclopropyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one (preparation #24) (1.0 g, 4.1 mmol) was added water (0.8 mL, 44 mmol). After about 5 minutes, DCM (5 mL) was added. All the solids dissolved. The reaction mixture was stirred at room temperature for about 16 hours. Purification on a Biotage silica gel column eluting with DCM/EtOAc (1:0 to 1:1) afforded (3S,7R,7aR)-7a-cyclopropyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (1.29 g, 2.98 mmol) as a white solid. RP-HPLC (Table 1, Method a) Rt 2.14 min; m/z: (M+H)+ 433.
Reaction SMILES: [C:1]1([CH3:7])C=CC=C[CH:2]=1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=[CH:16][CH:17]=1)=[O:11].S(Cl)(Cl)=O.C[N:26](C=O)C>C(Cl)(Cl)Cl>[CH:1]1([NH:26][C:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][CH3:8])=[O:11])=[O:20])[CH2:2][CH2:7]1
Reactant: Cc1ccccc1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc(C(=O)NC2CC2)c1

Procedure:
Toluene solution of 3-(Methoxycarbonyl)benzenecarboxylic acid, thionyl chloride and DMF (a catalytic amount) were heated under stirring. The reaction solution was dissolved in chloroform after evaporation under reduced pressure. After cyclopropylamine and triethylamine were added thereto and the whole was stirred at room temperature to obtain methyl 3-[(cyclopropylamino)carbonyl]benzoate.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]O)[CH2:14][CH2:13]1.CC(N(C)C)=[O:23]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:17][CH2:16][CH:15]([CH:18]([OH:23])[CH3:19])[CH2:14][CH2:13]3)=[N:3][N:4]=2)[CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: OCCC1CCNCC1
Reactant: Fc1ccc2nnc(Cl)n2c1
Product: CC(O)C1CCN(c2nnc3ccc(F)cn23)CC1
Temperature: 170 °C
Yield: 41 %

Procedure:
A mixture of Intermediate 24b (542 mg, 3.17 mmol) and 4-piperidine-ethanol (1.54 g, 11.9 mmol) in DMA (10 mL) was heated in the microwave at 170° C. for 3 h. The cooled mixture was applied to an SCX-2 cartridge (50 g), washing with methanol then eluting basic components with 0.4-2 M ammonia in methanol. Product containing fractions were combined and concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, to give the title compound as a pale brown solid (324 mg, 41%). LCMS (Method 3): Rt 2.28 min, m/z 265 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.[NH2:38][CH2:39][C:40]#[N:41]>>[C:39]([CH2:40][NH:41][C:23](=[O:25])[CH:22]([N:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[CH:7]1[CH2:6][C:5]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[N:38]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: N#CCN
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCC#N)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with amino acetonitrile hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4](OCC(C)C)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+].[C:29](#N)C>CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([NH:16][CH2:21][CH:20]([CH3:29])[CH3:19])[N:3]=1
Reactant: c1ccncc1
Reactant: CC(C)COc1nc(Cl)ccc1C(N)=O
Reactant: CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)CNc1nc(Cl)ccc1C#N
Temperature: 55 °C
Yield: 91 %

Procedure:
To a solution of 6-chloro-2-isobutoxy-nicotinamide (3, 2.39 g, 10.4 mmol) in acetonitrile (anhydrous, 150 mL) were added pyridine (6.75 mL, 83.5 mmol) and POCl3 (3.82 mL, 41.7 mmol). The reaction was heated at 55° C. for 3 hours. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc (60 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×60 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 2%-30% EtOAc/hexanes gradient, to afford 2 g (91% yield) of the title product.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].[CH3:13][Mg+].[Br-]>>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]([OH:7])[CH3:13])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: C[Mg+]
Reactant: Cc1cc(C=O)c(F)c(Br)c1N
Agent: [Br-]
Product: Cc1cc(C(C)O)c(F)c(Br)c1N

Procedure:
Using the method of Example 19, 4-amino-3-bromo-2-fluoro-5-methylbenzaldehyde is reacted with MeMgBr to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][OH:14])=[CH2:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][C:11]([CH2:13][O:14][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH2:12])=[CH:15][CH:16]=1
Reactant: C=C(CO)CCOCc1ccc(OC)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(CCOCc1ccc(OC)cc1)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Combine 4-(p-methoxybenzyloxy)-2-hydroxymethylbut-1-ene (0.77 g, 3.46 mmol) with pyridine (3 mL) and add dropwise benzoyl chloride (603 μL, 5.2 mmol). Stir the mixture at room temperature for 20 hours. Dilute the reaction mixture with diethyl ether (100 mL) and washed 3X with saturated sodium bicarbonate solution, dry over MgSO4 and concentrate in vacuo. Chromatograph on silica gel eluting with 1/9 ethyl acetate/hexane to give the title compound as an oil. Rf =0.28, silica gel, 1/9 ethyl acetate/hexane.
Reaction SMILES: COCCO[AlH2-]O[CH2:8][CH2:9][O:10][CH3:11].[Na+].[C:13]1(C)[CH:18]=CC=[CH:15][CH:14]=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CO>[CH3:11][O:10][C:9]1[CH:8]=[C:18]([CH2:13][CH2:14][CH3:15])[CH:24]=[CH:23][C:22]=1[CH2:21][OH:20]
Reactant: Cc1ccccc1
Reactant: C1CCOC1
Reactant: COCCO[AlH2-]OCCOC
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCc1ccc(CO)c(OC)c1
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
Red-Al/toluene solution (66.5% content, 2.05 g) was slowly added to a tetrahydrofuran (3 mL) solution of the compound (1.00 g) prepared in Example 43 at an internal temperature of 5° C., followed by stirring at an internal temperature of about 35° C. for about 2.5 hours. Methanol (0.5 mL) was added to the reaction solution at an internal temperature of 9° C. to stop the reaction. The reaction solution was poured into a 50% aqueous potassium sodium tartrate tetrahydrate solution, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, dried, and concentrated, to thereby obtain the title compound (0.91 g) having the following physical properties.
Reaction SMILES: Cl[C:2]1[C:3](=[O:24])[O:4][C:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2CCCCC=2)(C2CCCC2)CC=1O.ClC1C=CC2N(C(C)C)C(S)=NC=2C=1.[N:61]1[CH:66]=[CH:65][C:64]([C:67]2[NH:68][C:69]([SH:72])=[N:70][N:71]=2)=[CH:63][CH:62]=1>>[CH:18]1([CH2:17][CH2:16][CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:24])[C:2]([S:72][C:69]3[NH:68][C:67]([C:64]4[CH:65]=[CH:66][N:61]=[CH:62][CH:63]=4)=[N:71][N:70]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(CCCCC2CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Agent: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Product: O=C1OC(CCCCC2CCCCC2)(C2CCCC2)CC(O)=C1Sc1nnc(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-(4-cyclohexyl-butyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one (described in Step 2 of example C(32) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.
Reaction SMILES: C([C:3](CC)([NH:10][C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)C.[CH3:27][P:28](=[O:31])([O-:30])[O-:29]>Cl>[CH:23]1[C:24]2[C:19](=[CH:18][C:17]3[C:12]([C:11]=2[NH:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:20]=[CH:21][CH:22]=1.[CH3:27][P:28](=[O:29])([OH:31])[OH:30]
Reactant: CP(=O)([O-])[O-]
Reactant: CCC(CC)(Nc1c2ccccc2cc2ccccc12)c1ccccc1
Agent: Cl
Product: CP(=O)(O)O
Product: c1ccc(CNc2c3ccccc3cc3ccccc23)cc1
Yield: 103.9 %

Procedure:
A mixture of diethyl (9-anthracyl)-N-benzylamine-methylphosphonate (0.44 g) and Analar concentrated hydrochloric acid (10 ml) was stirred at gentle reflux for 5 h. Cooled, the solvent was then removed under reduced pressure. Water (10 ml) was added and the solvent was removed under reduced pressure. This was repeated a further four times to give (9-anthracyl)-N-benzylamine-methylphosphonic acid as a white solid (0.4 g), m.p. 168-170° C., λex (EtOH, nm) 332, λem 425.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])(C)(C)C.C(O[C:30](=[O:53])[CH2:31][C:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[S:40][C:41]([CH2:44][O:45]C3CCCCO3)=[N:42][N:43]=2)[CH:34]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:45][CH2:44][C:41]1[S:40][C:39]([C:35]2[CH:34]=[C:33]([C:32]3[CH2:31][C:30](=[O:53])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:20])([F:21])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)=[N:43][N:42]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(COC3CCCCO3)s2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3nnc(CO)s3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-5-(methyl-propyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J35) and 3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,3,4]thiadiazol-2-yl]-phenyl}-propionic acid tert-butyl ester (0.23 g) (Example K30) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (0.02 g).