Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[CH3:24][CH:25]([OH:28])[CH:26]=[CH2:27]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:27][CH2:26][CH:25]([OH:28])[CH3:24])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(C)O
Product: CC(O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and but-3-en-2-ol analogous to Example 44: (M−1)−=299; HPLC retention time=1.16 min (method B)
Reaction SMILES: C([C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[CH:14]C=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#N.Cl.[C:19]([OH:22])(=[O:21])[CH3:20]>O>[CH:13]1[C:10]2[CH:11]=[CH:12][C:6]3[CH:5]=[CH:4][CH:3]=[CH:17][C:7]=3[S:8][C:9]=2[CH:16]=[C:20]([C:19]([OH:22])=[O:21])[CH:14]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1C=C2

Procedure:
2.0 G. 3-cyanodibenzo[b,f]thiepin are refluxed in a mixture of 25 cc. concentrated HCl and 25 cc. glacial acetic acid for 19 hours; the acid separates from the hot solution. After cooling, the mixture is diluted with water and the light yellow solid is filtered and washed well with water. The yield of dibenzo[b,f]thiepin-3-carboxylic acid is 2.07 g. (95.8%), m.p. 251° C.-254° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[OH:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:13]=1[C:14]#[N:15]>CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[C:14]([C:13]1[CH:16]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][C:12]=1[O:11][C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])#[N:15]
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: N#Cc1cc(Oc2ccccc2)ccc1O
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2C#N)CC1
Yield: 105.2 %

Procedure:
4-Methyl-1-piperidinecarbonyl chloride (1.18 ml, 8.01 mmol) was added under a nitrogen atmosphere at room temperature to a solution of 2-hydroxy-5-phenoxybenzonitrile (1.53 g, 7.26 mmol) and 4-dimethylaminopyridine (0.976 g, 7.99 mmol) in 50 ml of benzene and the resulting solution refluxed for 1 hour. The reaction mixture was washed with 1N HCl. The benzene layer was separated, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 2.57 g of a white crystalline solid. Recrystallization of this solid from diisopropyl ether-hexane gave the title compound as a white crystalline solid (1.59 g, 65%), mp 54°-58° C.
Reaction SMILES: C([CH2:4][SiH:5](Cl)[Cl:6])C=C.[CH2:8]([Mg]Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CCCCCC>O1CCCC1>[CH3:4][SiH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[Cl:6]
Reactant: C=CCC[SiH](Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCC[SiH](C)Cl

Procedure:
was prepared as follows. Allylmethyldichlorosilane (0.69 moles, available from the Aldrich Chemical Co., Milwaukee, Wis., USA) was put into a reaction flask with 250 milliliters of tetrahydrofuran (THF). One molar octadecylmagnesium chloride (0.65 moles) in THF was added portionwise to the flask while the mixture was stirred and cooling to a temperature range of about -10° to +5°. The temperature of this mixture was allowed to increase to 24°. Hexane was added to the mixture, and the solid filtered off. The filtrate was evaporated on a rotary evaporator to leave an oil. The oil was vacuum-distilled, providing 134.7 g (55.8% relative to the theoretical yield) of ally methyl octadecyl-chlorosilane (compound A) as a clear, colorless oil. The boiling point of compound A was 188°/0.1-191°/0.2 mm, and gas chromatography/mass spectrometry (GC/MS) showed 100% compound A.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15](I)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:15]([C:35]4[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=4)=[CH:16][C:9]=23)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(-c3cccc(F)n3)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4cccc(F)n4)ccnc3n2S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of Example 309C (4 g, 7.09 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.63 g, 8.51 mmol), Pd(Ph3P)4 (0.410 g, 0.355 mmol), and an aqueous solution (15 mL) of sodium bicarbonate (1.788 g, 21.28 mmol) in dimethylformamide (50 mL) was stirred at 80° C. overnight. The reaction mixture was cooled, treated with water, and extracted with ethyl acetate (three times). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated with a mixture of ethyl acetate and petroleum ether (1:1). The solids were filtered and vacuum oven-dried to give the title compound. MS (ESI+) m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([SH:15])[CH2:13][SH:14])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:29][O:28][C:24]1[CH:23]=[C:20]([CH:21]2[S:15][CH:12]([C:5]3[CH:6]=[C:7]([O:10][CH3:11])[C:8]([OH:9])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:13][S:14]2)[CH:19]=[C:18]([O:17][CH3:16])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COc1cc(C(S)CS)cc(OC)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C2CSC(c3cc(OC)c(OC)c(OC)c3)S2)cc(OC)c1O

Procedure:
1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40) (2.10 g, 8.54 mmole), 3,4,5-trimethoxybenzaldehyde (24) (1.28 g, 6.57 mmole) and 0.857 g of pyridinium paratoluene sulfonate are added to 60 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope overnight. The benzene is removed in vacuo, and the remaining oil is extracted into 10% NaOH which was washed with diethylether. The basic layer is reacidified with 10% HCl and the desired product is extracted into ethyl acetate. The organic layer is dried over MgSO4, filtered, and evaporated in vacuo to an oil which is purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.2 cis/trans ratio after the first recrystallization (1.287 g, 59%). The trans isomer is isolated after six additional recrystallizations from methanol.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([OH:20])(=O)[C:17]#[CH:18].[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.ClCCl.CO>ClCCl>[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]([NH:27][C:16](=[O:20])[C:17]#[CH:18])=[CH:25][CH:26]=1
Reactant: C#CC(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
9.38 g (45.5 mmol) of DCC are added batchwise to a solution of 2.89 g (41.36 mmol) of propynoic acid in 100 mL dichloromethane at −15° C. and stirred for 1 hour. Then a solution of 7 g (41.36 mmol) of biphenyl-4-ylamine-15° C. is added dropwise to 30 mL dichloromethane and stirred for 2 hours. After this time, the cooling bath is removed and the reaction mixture is allowed to come up to ambient temperature. 20 g of CELITE® filter aid is added to the reaction mixture and it is then filtered. The filtrate is evaporated down in vacuo. The residue is combined with acetonitrile and stirred. The suspension is filtered, the filtrate is evaporated down and the residue is stirred with petroleum ether and pentane. The solid is isolated by filtration. Yield: 5.5 g (60.1% of theory); C15H11NO (M=221.26); calc.: molecular ion peak (M+H)+: 222; found: molecular ion peak (M+H)+: 222; Rf value: 0.7 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: N([O-])=[O:2].[Na+].[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])N)=[CH:10][CH:9]=1)([O-:7])=[O:6].Cl.OS(O)(=O)=O>O>[OH:2][CH:13]([CH2:12][C:11]1[CH:18]=[CH:19][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=1)[C:15]([OH:17])=[O:16]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of sodium nitrite (4.6 g) in water (18 ml) was added dropwise at 0° C. over 20 minutes to a stirred mixture of p-nitrophenylalanine (6.3 g, Fluka) c.HCl (3.1 ml), 5% aqu. H2SO4 (80 ml) and water (10 ml). When addition was complete, the mixture was stirred at 0° C. for 1 hour, then allowed to warm to room temperature over 2 hours. The mixture was extracted with ethyl acetate (×4) and the extracts dried over MgSO4 and evaporated in vacuo to give the desired product as a white solid (3.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](OCC)=[O:34].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:32]([CH2:31][CH2:30][CH2:29][CH2:28][C:20]3[S:19][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[C:33]2=[O:34])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCCc1nc2ccccc2s1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2nc3ccccc3s2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 6-(benzothiazol-2-yl)hexanoate (1.5 eq., prepared according to the procedure of Example 13 in JP, A, 8-208631 (1996)) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(benzothiazol-2-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 167.5 to 169.5° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([NH:12][CH2:13][CH2:14][NH:15]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[ClH:31]>C(O)(=O)C>[ClH:31].[NH2:15][CH2:14][CH2:13][NH:12][C:10](=[O:11])[O:9][CH2:8][C:7]1[CH:29]=[CH:30][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(NCCNC(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(=O)O
Product: NCCNC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 355 mg of 1,2-di(4-nitrobenzyloxycarbonylamino)ethane, 4 ml of acetic acid and 0.5 ml of 11M-hydrochloric acid was heated under reflux for 2.5 hours, and then lyophilised in vacuo. The solid residue was partitioned between ethyl acetate and water, and the insoluble material removed by filtration. The aqueous layer was separated and washed with ethyl acetate and then lyophilised to afford 139 mg of an off-white solid. Recrystallisation from ethanol afforded 100 mg of the title compound, m.p. 170°-171° C. dec.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=[NH:5])#[N:2].Cl.[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O>C(OCC)(=O)C>[ClH:14].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:1]([NH:3][C:4]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[NH:5])=[NH:2])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#CNC(=N)NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N=C(NCc1ccc(Cl)c(Cl)c1)NC(=N)Nc1ccc(Cl)cc1
Yield: 130.2 %

Procedure:
To 20 g of N1 -cyano-N3 -(3,4-dichlorobenzyl)-guanidine and 13.5 g of 4-chloroaniline hydrochloride, 200 ml of water was added, which was heated and refluxed for 2 hours. When cooled gradually after reaction, crystals was precipiated. After filtering the crystals, by drying the crystals obtained by heat treatment in 200 ml of ethyl acetate, 21.8 g of the captioned compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][CH:12]=[N:14][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: O=c1nc[nH]c2ccc(I)cc12
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A solution of 2-amino-5-iodo-benzoic acid (5.00 g, 19.0 mmol) and formamide (3.43 g, 76.0 mmol) were heated to 150° C. for 4 hours and then cooled to room temperature. Water was added and the solution was filtered and washed with water several times to give 3.6 g (70%) of 6-iodo-1H-quinazolin-4-one. 1H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 8.09 (dd, 1H, J=2.0, 8.8 Hz), 7.45 (d, 1H, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH:8]=[C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:6][CH2:5]2
Reactant: C1CCNC1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Clc1cc(Cl)c2c(c1)CCC(N1CCCC1)=C2

Procedure:
30.0 g of 6,8-dichloro-3,4-dihydro-2(1H)-naphthalenone were boiled at reflux for 2 hours in 250 ml of benzene and 11.5 ml of pyrrolidine in the presence of 0.5 g of anhydrous p-toluenesulphonic acid. For purification, the 1-(6,8-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine obtained was triturated with 150 ml of isopropyl ether. The filtered-off solid exhibits a melting point of 84°-86°. A further portion of melting point 84.5°-85.5° can be isolated from the mother liquors. The two portions were combined and, after recrystallization from isopropyl ether, there was obtained 1-(6,8-dichloro-3,4-dihydro-2-naphthyl)pyrrolidine of melting point 85.5°-86°.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=O)[N:6]2[CH2:9][CH2:10][NH:11][CH2:12][CH:5]2[C:4](=O)[NH:3]1.B.C1COCC1>Cl>[CH3:1][C@@H:2]1[CH2:7][N:6]2[CH2:9][CH2:10][NH:11][CH2:12][CH:5]2[CH2:4][NH:3]1
Reactant: C[C@H]1NC(=O)C2CNCCN2C1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H]1CN2CCNCC2CN1
Yield: 81.2 %

Procedure:
To a flask containing(3R)-3-methyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione(D98, 353 mg, 1.927 mmol) was added 1M BH3-THF solution (20 mL) and it was heated to reflux for 20 h. MS analysis: m/z=156 (M+1 of the target product).To the reaction were added at 0° C. 10 mL of 6M HCl and it was heated to 90° C. for 20 h. The reaction mixture was purified by SCX, obtaining 243 mg of the target compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([O:12][CH3:13])[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:15]>C(O)CCC>[CH3:13][O:12][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:15])[C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: COc1ncnc(F)c1C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Product: COc1ncnc(N)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-6-methoxy-5-(trifluoromethyl)pyrimidine (N-2) (1.10 g, 5.61 mmol) in n-butanol (4 mL) in a pressure vessel, ammonium hydroxide (5 mL) is added and the resulting mixture is stirred at 90° C. for 1 h. The mixture is allowed to cool to RT, quenched with water, and extracted with ethyl acetate (100 mL×2). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo to afford the product 6-methoxy-5-(trifluoromethyl)pyrimidin-4-amine (N-3) as an off-white solid. The product is used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].Cl.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=2[O:30][CH3:31])[CH2:19][CH2:18]1>CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:28][C:24]3[C:23]([O:30][CH3:31])=[C:22]([O:21][CH2:20][CH:17]4[CH2:19][CH2:18]4)[CH:27]=[CH:26][N:25]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COc1c(OCC2CC2)ccnc1CCl
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2nc(SCc3nccc(OCC4CC4)c3OC)[nH]c2cc1C
Yield: 100.8 %

Procedure:
To a solution of 5-carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.58 g, 2.6 mmol) in methanol (25 ml) aqueous NaOH (1.0 ml 5M, 5.0 mmol) and 4-cyclopropylmethoxy-3-methoxy-2-chloromethyl pyridine hydrochloride (prepared according to processes known per se.) (0.63 g, 2.4 mmol) dissolved in methanol (25 ml were added in the given order. The mixture was refluxed for one hour whereupon the solution was evaporated. The residue was partitioned between methylene chloride and water. After separation the organic solution was dried over Na2SO4 and evaporated giving a yellow syrup (1.0 g, 100%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].I[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>C(N(CC)CC)C.[Cu](I)I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: Nc1ccccc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
32 mg of copper iodide and 140 mg of bis(triphenylphosphine) palladium chloride, then 2.3 ml of 1-hexyne were added to a solution of 4.4 g of 2-iodoaniline in 100 ml of triethylamine and the mixture was stirred for 15 hours at ambient temperature. After evaporation to dryness, the residue was taken up in ether and the insoluble part was filtered out and washed with ether. The filtrate was evaporated to dryness and the residue was chromatographed on silica (eluant: hexane-ethyl acetate (9-1)) to obtain 3.27 g of the desired product.
Reaction SMILES: [CH2:1]([C:5]12[CH2:18][CH2:17][C:16](=[O:19])[CH:15]=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].[Br:27]Br>C(Cl)(Cl)(Cl)Cl>[Br:27][C:15]1[C:16](=[O:19])[CH2:17][CH2:18][C:5]2([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:20][CH3:21])=[CH:11][CH:12]=1)[CH2:7][CH2:6]2
Reactant: CCCCC12CCC(=O)C=C1c1ccc(OC)cc1CC2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone (31 mg, 0.109 mmol) and NaHCO3 (46 mg, 0.545 mmol) in CCl4 (0.25 mL) was stirred at room temperature while Br2 (0.0056 mL, 0.109 mmol) was added by syringe. A gummy precipitate formed which slowly dissolved. After stirring at room temperature for 15 minutes, the mixture was partitioned between EtOAc (4 mL) and aqueous Na2SO3 (4 mL). The organic phase was washed with brine, dried over MgSO4, filtered, and evaporated under vacuum to an oil. The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 5% EtOAc in CH2Cl2. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 4-bromo-10a-butyl-7-methoxy-1,9,10,10a-tetrahydro-3(2H)-phenanthrenone as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.F[B-](F)(F)F.C1(C([N+:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]1([CH:7]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)[n+]2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccccc1)c1ccccn1
Temperature: 0 °C
Yield: 43.6 %

Procedure:
Ethyl phenylacetate (3.13 g, 19 mmol, 1.0 equiv) was added in a dropwise manner to a solution of LDA (19 mmol, 1 equiv) in THF (30 mL) at −78° C. The resultant solution was maintained at to −78° C. for 25 minutes, and then warmed to 0° C. for 10 minutes. Triphenylmethylpyridinium tetrafluoroborate (7.8 g, 19 mmol, 1.0 equiv) was added in one portion. The reaction mixture was allowed to warm to 23° C. overnight and then concentrated. The residue was partitioned between saturated aqueous ammonium chloride (50 mL) and ethyl acetate (50 mL). The layers were separated, and the aqueous layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (25% THF/hexanes) to afford ethyl α-phenylpyridylacetate (2.0 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:32])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:32])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 135 mg (0.46 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 100 mg (0.63 mmol) of 5-amino-2-methylquinazoline and 0.23 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 260 mg of resultant crude imine are cyclized, in the same way as in Example 1, at −30° C. using 5 ml (5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 56 mg of product.
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28](S(C)(=O)=O)[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][N:28]2[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:26][CH2:25][CH2:24][C@H:23]4[CH3:27])[CH:17]=[C:12]3[CH:11]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:33])([F:1])[CH2:3][CH2:4]2)=[O:9])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCCN1CCCOc1cnc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-{1-methanesulfonyl-5-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-1H-pyrrolo[2,3-b]pyridin-2-yl}-methanone (example 20), sodium hydride and cyclopropylmethyl bromide, to give the desired product as a light yellow oil (53%).