Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:6][NH2:7].[N-:12]([C:15]#[N:16])[C:13]#[N:14].[Na+]>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH2:6][NH:7][C:15]([NH:12][C:13]#[N:14])=[NH:16]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: N#C[N-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: N#CNC(=N)NCc1ccc(Cl)c(Cl)c1
Yield: 79.2 %

Procedure:
Putting 63.7 g (300 mM) of 3,4-dichlorobenzylamine hydrochloride and 30.9 g (1.1 eq.) of sodium dicyanamide in 950 ml (15 V) of acetonitrile, the mixture was heated and refluxed for 3.5 hours. Distilling away the solvent, 600 ml of water was added to the residue (white solid) to disperse and wash. Obtained crystals were filtered off, and dispersed and washed in 600 ml of dichloromethane. Since residue of amine was recognized, the crystals were dispersed and washed again in 600 ml of water and 500 ml of dichloromethane. Crystals were filtered off, and dried overnight at 60° C., and 57.7 g (78.9%) of the captioned compound was obtained.
Reaction SMILES: C(O[C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=O)C.Cl.[OH:18][C@H:19]1[CH2:24][CH2:23][C@H](N)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:18][C@H:19]1[CH2:24][CH2:23][C@H:4]([N:6]2[C:7](=[O:16])[C:8]3=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]3[C:10]2=[O:11])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1

Procedure:
N-Ethoxycarbonylphthalimide (100 g; 0.46 mol) was added to a mixture of trans-4-hydroxycyclohexylamine hydrochloride (69 g; 0.46 mol), potassium carbonate (158 g; 1.15 mol) and water (1 L) at room temperature. After stirring for 3 h the title compound (95 g) was isolated by filtration, washing with water then ethyl acetate.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].Cl>O1CCCC1>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][C:13]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)Nc1ccccc1N
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)n1c(=O)[nH]c2ccccc21

Procedure:
To a solution of tert-butyl-(2-nitrophenyl)-amine (1.27 g, 6.5 mmol), 5% palladium on carbon (0.5 g), and sodium borohydride (0.49 g, 13.1 mmol) in tetrahydrofuran (20 mL) was added methanol (10 mL) in a dropwise manner. Upon completion of the reaction, it was filtered through a pad of Celite and the filtrate was poured into a saturated aqueous solution of ammonium chloride (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo to give N-tert-butyl-benzene-1,2-diamine which was used in the next step without further purification. A solution of N-t-butyl-benzene-1,2-diamine (1.1 g, 6.7 mmol) and carbonyldiimidazole (1.63 g, 10 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred at room temperature for 12 hours. Upon completion, the reaction was poured into a 1 N aqueous solution of hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 50% ethyl acetate in hexane) to give 1-tert-butyl-1,3-dihydro-benzimidazol-2-one as an off-white solid. MS (ES) m/z 191.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([S:16][CH2:17][C:18]([O:20]C)=O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH3:22]C(C)([O-])C.[K+].CI.O>O1CCCC1>[CH3:22][N:1]1[C:2]2=[C:3]3[C:8](=[N:9][C:10]4[CH2:11][CH2:12][CH2:13][CH:14]([C:15]=42)[S:16][CH2:17][C:18]1=[O:20])[CH:7]=[CH:6][CH:5]=[CH:4]3
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CSC1CCCc2nc3ccccc3c(N)c21
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CSC2CCCc3nc4ccccc4c1c32
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
To a mixture of methyl [(9-amino-1,2,3,4-tetrahydroacridin-1-yl)thio]acetate (5.06 g) in tetrahydrofuran (100 ml) was added potassium t-butoxide (2.3 g). The mixture was stirred for 30 mins and methyl iodide (1.6 ml) was added. Stirring was continued for 2 hrs, and the reaction mixture was poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic extracts were purified by flash chromatography (ethyl acetate/dichloromethane) to give 3.42 g (72%) of the 1,3,4a,5,6,7-hexahydro-1-methyl-2H-quino-[4,3,2-ef][1,4]benzthiazepin-2-one, mp 241°-245° C. (dec.).
Reaction SMILES: Cl.Cl.[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][NH2:13].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][NH:13][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14]
Reactant: NCc1nc2ccccc2[nH]1
Reactant: COC(C=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(CNCc1nc2ccccc2[nH]1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a MeOH 150 mL suspension of 1-(1H-benzimidazol-2-yl)methanamine dihydrochloride (4.0 g, 18.2 mmol) were added dimethoxyacetaldehyde (1.89 g, 18.2 mmol, 60 wt. % solution in water), sodium acetate (7.45 g, 91 mmol) and sodium cyanoborohydride (9.09 mL, 9.09 mmol, 1.0 M THF solution). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and reconstituted in DCM (150 mL). The resulting suspension was filtered. The filtrate was concentrated and chromatographed on silica gel with a gradient solvent mixture (5% MeOH-DCM to 15% MeOH-DCM over 15 CV) to give the title compound as oil (3.1 g). LC/MS: m/z 205(M+-OMe). 1H-NMR (CDCl3, 500 MHz) δ 3.02 (d, 1H), 3.36 (s, 6H), 4.40 (s, 211), 4.52 (t, 1H), 7.28-7.32 (m, 2H), 7.58-7.62 (m, 2H), 8.78-8.92 (br.s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4F)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[C].[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc(C=CCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(CCCc2ccccc2)c1
Yield: 90.8 %

Procedure:
A solution of 3-(3-phenyl-1-propenyl)aniline (3.6 g) in 50 ml of ethanol was subjected to catalytic reduction using 1 g of 10% palladium-carbon. After removal of the catalyst by filtration, the solvent was removed under reduced pressure. The residue was distilled under reduced pressure to give 3.3 g of 3-(3-phenylpropyl)aniline (yield, 92%). B.P. 122°-126° C./0.08 mmHg.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([OH:20])=[O:19])[C:13](=[O:21])[NH:12]2)=[CH:7][CH:6]=1)#[N:4].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@@:11]2([CH3:22])[C:15](=[O:16])[N:14]([CH2:17][C:18]([O:20][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:19])[C:13](=[O:21])[N:12]2[CH2:3][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)#[N:4]
Reactant: C[C@@]1(c2ccc(C#N)cc2)NC(=O)N(CC(=O)O)C1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@]1(c2ccc(C#N)cc2)C(=O)N(CC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
7.73 g (160.8 mmol) of sodium hydride were added to a solution of 20 g (73.1 mmol) of ((S)-4-(4-cyanophenyl)-4-methyl-2,5-dioxoimidazolidin-1-yl)acetic acid in 120 ml of absolute DMF with ice-cooling. After stirring at room temperature for 30 min, 19 ml (160.8 mmol) of benzyl bromide were added. The reaction mixture was stirred at room temperature for 2 h, allowed to stand overnight, the solvent was removed in vacuo and the residue was chromatographed on silica gel using heptane/ethyl acetate (2:1). 11.43 g (35%) of 8.1 were obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]1(O)[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1)[CH3:3].CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][C:4]1([N:2]([CH3:3])[CH3:1])[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][CH:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]3=[O:26])=[CH:12][C:11]=2[F:27])[CH:6]([CH3:28])[CH2:5]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(N(C)C)CC3C)c(F)c2)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(=O)NCC1CN(c2ccc(N3CCC(F)(N(C)C)CC3C)c(F)c2)C(=O)O1
Yield: 62 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(4-(N,N-dimethylamino)-methyl-4-hydroxy piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.22 mmol) with DAST (1.53 mmol) in dichloromethane (10 ml) at a temperature 0° C. for one hour and by purifying the compound by silica gel column chromatography in 62% yield.
Reaction SMILES: CS(O)(=O)=O.C(OC([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34](=[NH:36])[NH2:35])[CH:30]=2)[CH:25]=1)=[O:22])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[BrH:45].C(O)(=O)C>C(O)(=O)C>[BrH:45].[BrH:45].[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]([O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:34](=[NH:35])[NH2:36])[CH:30]=2)[CH:25]=1)=[O:22]
Reactant: N=C(N)c1ccc2cc(OC(=O)C3CCCN3C(=O)OCc3ccccc3)ccc2c1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: N=C(N)c1ccc2cc(OC(=O)C3CCCN3)ccc2c1

Procedure:
To a solution of 1.5 g of 6-amidino-2-naphthyl 1-benzyloxycarbonylpyrrolidine-2-carboxylate methanesulfonate in 10 ml of acetic acid, was added 1 ml of anisole. To the mixture, while cooling in ice and stirring, was added 3 ml of a 30% HBr/acetic acid solution. Thereafter the resulting mixture was stirred overnight at room temperature. The precipitate was collected by filtration and washed sufficiently with ethyl ether and acetone. Recrystallization from a mixture of methanol and ethyl ether gave 1.1 g of 6-amidino-2-naphthyl pyrrolidine-2-carboxylate dihydrobromide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3OCCO[C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.ClC1N=C(Cl)C(F)=CN=1.NC1C=C(C=CC=1)[CH2:33][OH:34]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:33][OH:34])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1
Reactant: Nc1cccc(CO)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Fc1cnc(Cl)nc1Cl
Product: OCc1cccc(Nc2nc(Cl)ncc2F)c1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 3-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N4-[3-(hydroxymethyl)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.45 (bs, 1H), 7.96 (d, 1H, J=2.9 Hz), 7.65 (d, 1H, J=8.2 Hz), 7.34 (s, 1H), 7.31 (t, 1H, J=8.2 Hz), 7.07 (d, 1H, J=8.2), 4.52 (s, 2H)); 19F NMR (CDCl3): −44394 (s, 1F); LCMS: ret. time: 20.29 min.; purity: 100%; MS (m/e): 254 (MH+).
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[CH:38][C:27]=2[O:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([O-:33])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:41]=[C:40]([C:42]([F:45])([F:43])[F:44])[CH:39]=[CH:38][C:27]=2[O:28][C:29]2[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=2[C:31]([OH:33])=[O:32])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=C([O-])c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Br)cc1
Agent: OC(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccccc1Oc1ccc(C(F)(F)F)cc1NS(=O)(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
Benzhydrol 2-[2-(4-bromophenylsulfonamido)-4-trifluoromethylphenoxy]benzoate was dissolved in methylene chloride (5 mL) and stirred under argon at 0° C. Trifluoroacetic acid (5 mL) was added and the mixture was stirred in an ice bath for ten minutes. The solvents were evaporated and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid). Recrystallization from ethyl acetate/hexane gave the title compound; mp 167°-168° C.
Reaction SMILES: Cl.C([NH:21][C@H:22]1[C:35](=[O:36])[N:24]2[C:25]([C:32]([O-:34])=[O:33])=[C:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][S:28][C@H:23]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+](C)([O-])=O>[NH2:21][C@H:22]1[C:35](=[O:36])[N:24]2[C:25]([C:32]([OH:34])=[O:33])=[C:26]([CH:29]([CH3:31])[CH3:30])[CH2:27][S:28][C@H:23]12
Reactant: CC(C)C1=C(C(=O)[O-])N2C(=O)[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](N)[C@H]2SC1

Procedure:
A current of gaseous hydrogen chloride was passed for 15 minutes through a mixture of 541 mg of tert.-butyl DL cis 7-tritylamino-3-isopropyl-3-cepheme-4-carboxylate in 11 ml of nitromethane on an ice bath and the mixture was then evaporated to dryness. The residue was taken in ether and was vacuum filtered. The precipitate was washed with ether, dried and dissolved in 1 ml of water. The pH was adjusted to 4 with pyridine addition and the mixture was vacuum filtered. The crystals recovered were washed with water, then acetone and ether and dried to obtain 204mg of DL cis 7-amino-3-isopropyl-3-cepheme-4-carboxylic acid melting at 230°C with decomposition. The product occurred as colorless crystals slightly soluble in water, ethanol and acetone and insoluble in ether.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Cl:18])[CH:12]=1>CC(C)=O>[Cl:18][C:13]1[CH:12]=[C:11]([NH:10][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)[CH:16]=[CH:15][C:14]=1[OH:17]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Product: Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Cyanuric chloride (12.95 g, 70.0 mmol) was dissolved in acetone (200 mL), the solution was cooled to 0-5° C. with an ice bath, and 4-amino-2-chlorophenol (10.09 g, 70.0 mmol) in acetone (100 mL) was added. The mixture was stirred at 0-5° C. for 1 hour under nitrogen. The reaction mixture was extracted three times using dichloromethane; the combined organic layer were washed with brine and dried over sodium sulfate. The sample was concentrated in vacuo, and the resulting solid was dried overnight under vacuum to yield E6 (20.2 g, 99%); mp 180° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4(0.01 M, pH 3.2):CH3OH:CH3CN], 264 mm, Rt 11.6 min, 99.4% purity; MS (TOF ES+) m/z 293 (97.5), 291 (M+H, 100).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:20][C:21]([OH:23])=[O:22])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:26]>CO>[CH3:26][O:23][C:21](=[O:22])[CH2:20][N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=[C:9]1[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To [2-(4-methoxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid (3.4 g, 11.0 mmol) dissolved in anhydrous MeOH (200 mL) and cooled to 0° C. is added chlorotrimethylsilane (1.40 mL, 11.0 mmol). The mixture is refluxed for ˜12 h. The contents are concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (10% hexanes/ethyl acetate) to give-(2,5-Diphenyl-pyrrol-1-yl)-acetic acid methyl ester as a yellow solid (2.68 g), characterized by LCMS (Obs: 322.56, Cal: 321.14) and 1H NMR.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9]>ClCCl>[N:1]1([CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)CCN1CCOCC1
Reaction time: 72 h
Yield: 98.4 %

Procedure:
A solution of 4.9 ml (56 mmol) of morpholine in 50 ml of dichloromethane was treated dropwise with 5.0 ml (56 mmol) of methyl acrylate. The resulting solution was allowed to stand at ambient temperature for 3 days, after which it was concentrated in vacuo to an oil. Chromatography on silica gel using 0.5% methanol/2% isopropylamine in chloroform provided 9.54 g (99%) of the desired compound as a colorless liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[OH:7])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of (3RS)-3-[(2S)-1-[3(N-benzyl-N-methylcarbamoyl)propionyl]pyrrolidin-2-yl]-3-hydroxypropionic acid ethyl ester (230 mg) in acetone (1 ml) was cooled to -30° C. Excess Jones' reagent was added dropwise to the solution. The mixture was stirred for 1 hr at the same temperature, and for 1 hr at -20° C., and for 1 hr at -10° C. Isopropyl alcohol was added to the reaction solution. Water was added to the mixture. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (98 mg) having the following physical data:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[O:64]1[C:68]([C:69](O)=[O:70])=[CH:67][CH:66]=[N:65]1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:69]([C:68]5[O:64][N:65]=[CH:66][CH:67]=5)=[O:70])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1ccno1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2ccno2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and isoxazole-5-carboxylic acid (0.1 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-6-{[1-(isoxazol-5-ylcarbonyl)piperidin-4-yl]oxy}-7-methoxyquinazolin-4-amine as a white solid (0.110 g). 1H NMR Spectrum: (DMSO d6 373K) 1.88 (m, 2H), 2.09 (m, 2H), 3.61 (m, 2H), 3.84 (m, 2H), 3.96 (s, 3H), 4.78 (m, 1H), 6.87 (s, 1H), 7.29 (m, 1H), 7.29 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.93 (s, 1H), 8.39 (s, 1H), 8.64 (s, 1H), 9.28 (br s, 1H); Mass Spectrum: (M+H)+ 498.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[I:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][NH2:18])=[CH:13][CH:12]=1>C(O)(=O)C>[I:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][N:18]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:2])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNc1ccc(I)cc1
Solvent: CC(=O)O
Product: CC(=NNc1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.54 g (12.82 mmol) of acetophenone in 10 ml of 50% strength acetic acid is added to a solution of 2.0 g (8.546 mmol) of 4-iodophenylhydrazine in 30 ml of the same solvent. The mixture is stirred at room temperature, and a precipitate is formed. After 30 minutes, the precipitate is filtered off and thoroughly washed with water and then with cyclohexane. The residue is dried under high vacuum. This gives 1.95 g (68% of theory) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[NH:49][CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:36])([CH3:35])[CH2:32][CH2:31]2.[CH2:52]([O:59][C:60](=[O:68])[CH2:61][C@H:62]1[CH2:64][C@@H:63]1[C:65](O)=[O:66])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@@H:40]2[N:49]([C:65]([C@H:63]3[CH2:64][C@@H:62]3[CH2:61][C:60]([O:59][CH2:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[O:68])=[O:66])[CH2:48][CH2:47][C:46]3[N:45]=[C:44]([O:50][CH3:51])[CH:43]=[CH:42][C:41]2=3)=[O:39])[CH:29]=[C:30]2[C:34]=1[C:33]([CH3:35])([CH3:36])[CH2:32][CH2:31]2
Reactant: COc1ccc2c(n1)CCN[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Reactant: O=C(C[C@H]1C[C@@H]1C(=O)O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H]1CC(=O)OCc1ccccc1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
HATU (1450 mg, 3.81 mmol) was added to a solution of (R)—N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxamide (1083 mg, 2.93 mmol), (1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (687 mg, 2.93 mmol) and DIEA (1.022 mL, 5.87 mmol) in DMF (14.5 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water (120 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 37→58% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-((R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)cyclopropyl)acetate (1.60 g, 2.73 mmol, 93%) as a colorless amorphous solid.