Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10](O)=[O:11])=[CH:8][O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.[OH-].[Na+]>[CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[CH:8][O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nocc1C(=O)O
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCc1nocc1CO
Temperature: -10 °C
Yield: 73 %

Procedure:
To a solution of 3-butyl-isoxazole-4-carboxylic acid (27.8 g, 164 mmol in THF (495 mL) at −10° C. was added triethylamine (22.9 mL, 164 mmol) and then a solution of ethylchloroformate (15.7 mL, 164 mmol) in THF (85 mL) added keeping the temperature below −5° C. After 1 h the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (31.1 g, 821 mmol) in water (165 mL) added over 15 minutes keeping the temperature below 10° C. The mixture was then allowed to warm up to room temperature overnight and diluted with sodium hydroxide (2 N, 82 mL) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated to afford the title compound (18.6 g, 73%) which was obtained as a colorless liquid after kugelrohr distillation. Bp: 150° C. at 0.4 mbar. MS: m/e=150.1 [M]+.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:23])([F:22])[C:10]1[CH:11]=[C:12]([N:19]=[C:20]=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17].[NH2:24][C:25]([C:28]#[N:29])([CH3:27])[CH3:26]>O1CCCC1>[F:8][C:9]([F:22])([F:23])[C:10]1[CH:11]=[C:12]([N:19]2[C:28](=[NH:29])[C:25]([CH3:27])([CH3:26])[NH:24][C:20]2=[O:21])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(N)C#N
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=N
Temperature: 20 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
1 ml of triethylamine was added to a mixture of 49.6g of 3-trifluoromethyl-4-nitrophenyl isocyanate in 500 ml of tetrahydrofuran and then 18 g of 2-amino-2-cyanopropane were rapidly added thereto. The mixture was stirred for 72 hours at 20° C and was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 27 g of 1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4 -dimethyl-5-imino-imidazoline-2-one melting at 168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[C:6](=[CH:7][N:8]([CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=1)([O-])=O.[Cl-].[NH4+].[CH2:22](O)C.O>[Fe]>[N:15]1([CH2:14][CH2:13][N:8]2[CH:7]=[C:6]3[C:10]([CH:11]=[CH:12][C:4]([NH2:1])=[CH:5]3)=[N:9]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2nn(CCN3CCCC3)cc2c1
Reactant: CCO
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccc2nn(CCN3CCCCC3)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Nitro-2-(2-pyrrolidin-1-yl-ethyl)-2H-indazole (0.325 g, 1.18 mmol), iron powder (0.659 g, 11.8 mmol) and ammonium chloride (0.0317 g, 0.592 mmol) was suspended in a 4:1 ethanol/H2O solution and heated to reflux for 3 hours. The mixture was cooled to room temperature, the solvent were removed in vacuo and the residue stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes. The mixture was filtered through a plug of silica gel, rinsed with triethylamine/ethyl acetate (1/4) and the filtrate was concentrated to afford the title product. 1H NMR (300 MHz, DMSO-d6) ppm 1.31–1.52 (m, 6H) 2.40 (m, 4H), 2.78 (m, 2H), 4.38 (t, 2H, J=6.78), 4.79 (s, 2H), 6.55 (m, 1H), 6.72 (m, 1H), 7.29 (s, 1H), 7.89 (s, 1H); MS (DCI/NH3) m/z 245 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[CH:2]=[CH2:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[O:13][CH3:14])[NH2:10])[CH:2]=[CH2:3]
Reactant: C=CCc1cc([N+](=O)[O-])ccc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C=CCc1cc(N)ccc1OC
Temperature: 25 °C
Yield: 87.6 %

Procedure:
15.0 g of 1-allyl-2-methoxy-5-nitrobenzene, 33.4 g of ammonium chloride, and 17.5 g of iron were suspended in 270 ml of ethanol and 55 ml of water. The reaction solution was heated to reflux for 1 hour. Thereafter, the reaction solution was cooled to a room temperature, and insoluble matters were then removed by filtration. The filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 11.1 g of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]#[CH:17])=[C:6]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])[CH:7]=1.[NH2:18][C:19]1[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=1.CCCCCCCC>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH2:15][C:16]#[CH:17])=[C:6]([S:8]([NH:11][C:12]([NH:18][C:19]2[N:24]=[C:23]([Cl:25])[CH:22]=[C:21]([O:26][CH3:27])[N:20]=2)=[O:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1cc(Cl)nc(N)n1
Reactant: C#CCOc1ccc(C)cc1S(=O)(=O)N=C=O
Solvent: C1CCOC1
Solvent: CCCCCCCC
Product: C#CCOc1ccc(C)cc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.4 g of crude 5-methyl-2-propargyloxyphenylsulfonylisocyanate in 50 ml of absolute tetrahydrofuran is added dropwise at room temperature, within 10 minutes, to a solution of 3.7 g of 2-amino-4-chloro-6-methoxy-pyrimidine and 0.1 g of 1,4-diazadicyclo[2.2.2]-octane in 60 ml of absolute tetrahydrofuran, in the course of which the temperature rises slightly. The reaction solution is stirred for 18 hours at room temperature; it is then filtered, and concentrated by evaporation. The residue is crystallised from ethyl acetate to thus obtain 5.8 g of N-(5-methyl-2-propargyloxyphenylsulfonyl)-N'-(4-chloro-6-methoxy-pyrimidin-2-yl)-urea, m.p. 202°-204° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11])#[N:2].[CH3:12][C:13]([O:16][C:17](=[O:30])[N:18]([CH2:20][CH2:21][C@H:22](O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:19])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][C@@H:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:21][CH2:20][N:18]([CH3:19])[C:17](=[O:30])[O:16][C:13]([CH3:15])([CH3:14])[CH3:12])#[N:2]
Reactant: CN(CC[C@H](O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(C#N)c(O)c1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C#N)c(O[C@H](CCN(C)C(=O)OC(C)(C)C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.4 %

Procedure:
To a stirred mixture of 2-cyano-5-methoxyphenol (149 mg, 1.00 mmol) and [(3S)-3-hydroxy-3-phenylpropyl]methylcarbamic acid 1,1-dimethylethyl ester (265 mg, 1.00 mmol) in tetrahydrofuran (10 ml) under nitrogen was added triphenylphosphine (290 mg, 1.10 mmol) followed by diethyl diazodicarboxylate (192 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 24 h, then evaporated to dryness. The residue was eluted down a flash chromatography column using 30% ethyl acetate/isohexane as eluent to give 275 mg (69%) of the subtitle compound as an oil.
Reaction SMILES: O.[OH-].[Li+].[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:10][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=2[F:21])[CH2:8]1)#[N:5].Cl>CO.O>[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[C:28]4[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:29]=4[N:30]=[CH:31][N:32]=3)[CH:24]=[N:23]2)[CH2:8][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[F:21])[CH2:10]1)#[N:5]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)cc5F)C4)c3)ncnc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Lithium hydroxide monohydrate (0.21 g, 5.0 mmol) was added to a mixture of methyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoate (1.06 g) in methanol (15.0 mL) and water (3.0 mL). The reaction mixture was stirred at 40° C. overnight. The mixture was adjusted to pH 3 with aqueous HCl (1.00 N), and concentrated under reduced pressure to remove methanol. The solid formed was filtered and washed with water, and dried under reduced pressure to afford the crude product (0.95 g) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=548.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CC1(C)[O:24][C:23]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[CH:22][C:21](=O)[O:20]1>>[C:28]([C:27]1[CH:26]=[C:25]([C:23](=[O:24])[CH2:22][C:21]([NH:1][C:2]2[CH:3]=[C:4]([N:11]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12]3)[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[O:20])[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: Nc1cc(-n2ccc(CO)c2)ccc1[N+](=O)[O-]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Product: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(CO)c3)ccc2[N+](=O)[O-])c1

Procedure:
The title compound was prepared from [1-(3-amino-4-nitro-phenyl)-1H-pyrrol-3-yl]-methanol (Example F5) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) according to the general procedure M. Obtained as an orange solid (77 mg).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[N:11]=2)[CH:5]=1.ClC1N=C(C2C=[C:32](C=CC=2)[C:33]([OH:35])=[O:34])C=C(C)N=1>COCCN>[C:4]([O:35][C:33](=[O:34])[CH2:32][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH2:18][CH2:19][O:20][CH3:21])[N:11]=2)[CH:5]=1)=[O:22])([CH3:9])([CH3:5])[CH3:3]
Reactant: COCCNc1nc(C)cc(-c2cccc(C(=O)OC)c2)n1
Reactant: Cc1cc(-c2cccc(C(=O)O)c2)nc(Cl)n1
Agent: COCCN
Product: COCCNc1nc(C)cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
The title compound was prepared from 3-[2-(2-methoxy-ethylamino)-6-methyl-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(2-Chloro-6-methyl-pyrimidin-4-yl)-benzoic acid (1.49 g, 6 mmol) was heated in 2-methoxy-ethylamine (5.2 ml) to 80° C. for 2.5 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (20 ml) for 18 h at 40° C. to give the methyl ester as light yellow solid (1.29 g).] (1.29 g, 4.3 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a light yellow oil (1.44 g).
Reaction SMILES: [C:1]1([C:7]([NH:20][C:21]2[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH2:32][C:33]3[CH:38]=[C:37]([OH:39])[C:36]([O:40][C:41](=[O:43])[CH3:42])=[CH:35][C:34]=3[C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])/[C:27](O)=[O:28])[N:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:60]1([CH:66]([O:73][C:74]([C:76]2[N:77]3[C@H:80]([S:81][CH2:82][C:83]=2[CH2:84][S:85][C:86]2[N:91]4[N:92]=[C:93]([C:95]([O:97][CH:98]([C:105]5[CH:110]=[CH:109][CH:108]=[CH:107][CH:106]=5)[C:99]5[CH:104]=[CH:103][CH:102]=[CH:101][CH:100]=5)=[O:96])[N:94]=[C:90]4[N:89]=[C:88]([CH3:111])[CH:87]=2)[C@H:79]([NH2:112])[C:78]3=[O:113])=[O:75])[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:60]1([CH:66]([O:73][C:74]([C:76]2[N:77]3[C@H:80]([S:81][CH2:82][C:83]=2[CH2:84][S:85][C:86]2[N:91]4[N:92]=[C:93]([C:95]([O:97][CH:98]([C:105]5[CH:106]=[CH:107][CH:108]=[CH:109][CH:110]=5)[C:99]5[CH:100]=[CH:101][CH:102]=[CH:103][CH:104]=5)=[O:96])[N:94]=[C:90]4[N:89]=[C:88]([CH3:111])[CH:87]=2)[C@H:79]([NH:112][C:27](=[O:28])/[C:26](/[C:24]2[N:25]=[C:21]([NH:20][C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:22][CH:23]=2)=[N:30]\[O:31][CH2:32][C:33]2[CH:38]=[C:37]([OH:39])[C:36]([O:40][C:41](=[O:43])[CH3:42])=[CH:35][C:34]=2[C:44]([O:46][CH:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:45])[C:78]3=[O:113])=[O:75])[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: Cc1cc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(C(=O)OC(c3ccccc3)c3ccccc3)nc2n1
Reactant: CC(=O)Oc1cc(C(=O)OC(c2ccccc2)c2ccccc2)c(CO/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)OC(c2ccccc2)c2ccccc2)c(CO/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4cc(C)nc5nc(C(=O)OC(c6ccccc6)c6ccccc6)nn45)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To an ice-cooled solution of the product obtained in Step 3 (0.63 g) and (6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[-4.2.0]oct-2-ene-2-carboxylic acid diphenylmethyl ester (0.5 g) in dry dichloromethane (20 ml) was added dicyclohexylcarbodiimide (0.178 g), and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 0.15 g of the objective compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:14]([O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)[CH2:12][CH2:11]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of trans-4-(4-iodo-1H-pyrazol-1-yl)-cyclohexanol (1.00 g, 3.42 mmol), tert-butyldimethylsilyl chloride (1.03 g, 6.85 mmol), and DMAP (80 mg, 0.7 mmol), 1H-imidazole (699 mg, 10.3 mmol) in DCM (20 mL) was stirred RT for 20 min. The mixture was diluted with DCM and washed with saturated NaHCO3. The organic layer was dry-loaded onto silica gel. Flash chromatography (3% EtOAc:hexanes) afforded 1.37 g (98%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 0.05 (s, 6 H), 0.86 (s, 9 H), 1.33-1.47 (m, 2 H), 1.70-1.91 (m, 4 H), 1.96 (d, J=11.9 Hz, 2 H), 3.58-3.75 (m, 1 H), 4.11-4.21 (m, 1 H), 7.49 (s, 1 H), 7.92 (s, 1 H); MS (ESI): 407.05 [M+H]+; HPLC tR=3.22 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2].Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[N:16]=[C:15]([C:17]([N:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=3[OH:21])[CH2:27]2)=[O:19])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:3])[CH3:2]
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Agent: Cl
Product: CC(=O)NCCc1nc(C(=O)N2CCc3c(ccc(N(C)C)c3O)C2)c2ccccc2n1
Yield: 9 %

Procedure:
Reaction of 2-(2-(acetamido)ethyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 77 (9% yield) as brown oil. 1H NMR (300 MHz, CD3OD) δ 1.86 and 1.88 (2s, 3H), 2.62 and 2.66 (2s, 6H), 2.79 and 3.03 (2t, 2H), 3.26-3.30 (m, 2H), 3.54 and 4.14 (2t, 2H), 3.73-3.82 (m, 2H), 4.41 and 4.99 (2s, 2H), 6.35 and 6.79 (2d, 1H), 6.91 and 7.10 (2d, 1H), 7.67-7.77 (m, 1H), 7.88-8.07 (m, 3H); MS (ESI) m/z 434 ([M+H]+).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3[CH:19]([CH2:23][OH:24])[CH2:20][CH2:21][CH2:22][C:17]=3[N:16]=[C:15]2[CH:25]([CH3:27])[CH3:26])=[CH:9][CH:8]=1>ClCCl>[CH3:4][S:1]([O:24][CH2:23][CH:19]1[C:18]2[N:14]([CH2:13][C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)[C:15]([CH:25]([CH3:26])[CH3:27])=[N:16][C:17]=2[CH2:22][CH2:21][CH2:20]1)(=[O:3])=[O:2]
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(CO)CCC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(COS(C)(=O)=O)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mesyl chloride (0.874 mL) was added dropwise to a suspension of Intermediate 40 (2.98 g) in dichloromethane (100 mL) at 0° C. under N2. Once addition was complete, the reaction was allowed to stir at 0° C. for a further 30 minutes before the bath was removed and the solution warmed to RT. The reaction mixture was quenched with water, and the aqueous extracted with DCM. The combined organics were passed through a hydrophobic frit and concentrated under reduced pressure, azeotroped with MeOH and dried on the high-vac to give the title compound 3.44 g. LC/MS MH+ 397, Rt 1.78 min (5 minute run).
Reaction SMILES: O.[OH-].[Na+].[C:4]([OH:8])(=[O:7])[CH:5]=[CH2:6].Br[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C(OCC)(=O)C>[C:4]([O:8][CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)(=[O:7])[CH:5]=[CH2:6]
Reactant: BrCc1ccc2ccccc2c1
Reactant: C=CC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCc1ccc2ccccc2c1

Procedure:
To 200 ml of distilled water, 81.4 g of sodium hydroxide was added, and 147 g of acrylic acid was dropped thereto under storage in ice. To this, 42.4 g of benzyl tributyl ammonium chloride and 300 g of 2-bromomethyl naphthalene were added and reacted at 75° C. for 2 hours. After the reaction, 800 ml of a mixture of ethyl acetate/hexyane=2/8 (volum ratio) was added thereto, the organic phase was washed with 1% of aqueous solution of acidum hydrochloricum, 1% of tetramethylammonium hydroxy aqueous solution, and distilled water. To the organic phase, 0.01 g of p-benzoquinone as a polymerizable inhibitor was added and concentrated under vacuum so that the content of the solvent in the organic phase is 1% by mass or less, to thereby obtain the polymerizable monomer (A2). The viscosity of (A2) was 10.3 mPa·s at 25° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([CH3:24])[CH3:23])[CH2:12][C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([O:27][C:25](=[O:26])[C:22]([CH3:24])([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])[N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[CH:10][C:11]=2[CH2:12]1)[CH3:29]
Reactant: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2c(ccn2C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCC(c1ccccc1Cl)N1CCc2[nH]ccc2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
5-[1-(2-Chlorophenyl)-6-ethoxycarbonyl-6-methylheptyl]-4,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (1.0 g, 1.94 mmol) was dissolved in dichloromethane (40 mL) under an argon atmosphere. Trifluoracetic acid (4.0 mL, 40.7 mmol) was added to the solution. After 2 hours, the mixture was poured into ice/water (90 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/9 to 1/3) to afford 7-(2-chlorophenyl)-2,2 dimethyl-7-(1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-yl)-heptanoic acid ethyl ester (Compound Il, 330 mg, 41.2% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.93 (br, 1H), 7.53 (d, 1H, J=7.5 Hz), 7.35 (d, 1H, J=7.8 Hz), 7.26-7.13 (m, 2H), 6.58 (s, 1H), 5.93 (s, 1H), 4.16 (dd, 1H, J=9.3, 3.9 Hz), 4.10 (q, 2H, J=7.2 Hz), 3.75 (d, 1H, J=13.5 Hz), 3.39 (d, 1H, J=13.2 Hz), 2.80-2.56 (m, 4H), 2.04-1.78 (m, 2H), 1.44-1.39 (m, 2H), 1.21 (t, 3H, J=6.9 Hz), 1.26-1.16 (m, 4H), 1.11 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 178.01, 139.87, 134.94, 129.40, 129.22, 127.86, 126.81, 125.01, 116.45, 115.70, 105.69, 63.80, 60.37, 48.78, 48.29, 42.31, 40.81, 33.29, 26.15, 25.36, 23.95, 14.52. HRMS (DART-TOF): Calculated for C24H33ClN2O2 (M+H)+: 717.2303, 417.2295 found.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16](O)CO>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([I:14])[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: OCCO
Reactant: CCOc1c(C(C)=O)cc(Cl)c(F)c1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1I
Temperature: 0 °C
Yield: 110.6 %

Procedure:
A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (20.0 g, 58.4 mmol; Example 212, step 1) and 1,2-ethanediol (6.5 mL, 120 mmol) in toluene (190 mL) was treated with p-toluenesulfonic acid monohydrate (1.1 g, 5.8 mmol). The flask was fitted with a Dean-Stark trap that was filled with sieves, and refluxed for 3 h. The reaction mixture was cooled and added to ice cooled saturated sodium bicarbonate solution (250 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a crude orange oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (0%-20%) to give the desired product (22 g, 99%). LCMS for C12H14ClFIO3 (M+H)+: m/z=387.0; Found: 386.9.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][C@@H:10]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][N:8]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:24]([O:23][C:21]([N:8]1[CH2:9][C@H:10]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@H:7]1[C:6]([OH:28])=[O:5])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)[C@@H]1C[C@@H](CNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
Lithium hydroxide monohydrate (29 mg) was added to a stirred solution of trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-L-proline methyl ester (C, 204 mg) in tetrahydrofuran (1 mL)-methanol (1 mL)-water (1 mL) at 0° C. The mixture was stirred at room temperature for 4 hr. The reaction mixture was acidified with 10% citric acid and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (167 mg).