Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH3:32])[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][C:24](F)=[C:23](C(F)(F)F)[CH:22]=4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[N:40]1([CH2:44]CN2C=C(C3CCCCC3)N=C2C2CCNCC2)[CH2:43][CH2:42][CH2:41]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[N:17]([CH2:32][CH2:44][N:40]4[CH2:43][CH2:42][CH2:41]4)[CH:18]=[C:19]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[N:20]=3)[CH2:12][CH2:11]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: c1c(C2CCCCC2)nc(C2CCNCC2)n1CCN1CCC1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N)ncnc1N1CCC(c2nc(C3CCCCC3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile using 4-[1-(2-azetidin-1-yl-ethyl)-4-cyclohexyl-1h-imidazol-2-yl]-piperidine trifluoroacetate instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=435, obsd.=435).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=O)=[CH:8][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:24]2)=CC=1.O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](=[S:24])[NH2:12])=[CH:8][CH:7]=1
Reactant: NC(=O)c1ccc(OCCCCl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=S)c1ccc(OCCCCl)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-(3-Chloropropoxy)benzamide ax54 (1.0 g, 4.6 mmole, 1 eq) is dissolved in a 1:1 mixture of chloroform and toluene, 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (1.5 g, 3.7 mmole, 0.8 eq) is added. The reaction is stirred overnight at 85° C. Water is then added and the phases are separated. The organic layer is dried over magnesium sulfate and concentrated under reduce pressure. The crude material is purified by chromatography on silicagel (eluent: dichloromethane/methanol/ammonia 98:1.8:0.2) to provide 0.91 g of 4-(3-chloropropoxy)benzenecarbothioamide ax71 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:22]([O:29][C:30](=[O:36])[C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanyl-L-proline (4.3 g, 15 m mole), L-proline benzyl ester hydrochloride (3.7 g, 15.3 m mole) and HOBt (2.0 g, 15 m mole) were dissolved in methylene dichloride (40 ml). WSC (2.8 ml) was added dropwise to the above mixture while cooling to -15° C. and stirring. The reaction was carried out for 3 hours at a temperature of not more than 0° C., and then overnight at room temperature. The solvent was removed by distillation under reduced pressure leaving a residue. The residue was dissolved in ethyl acetate, and washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water, in order. The mixture was dried over anhydrous sodium sulfate. The thus obtained solution was distilled under reduced pressure leaving a residue. The residue was crystallized with a mixture of ethyl acetate and n-hexan to give a crystal of N-t-butyloxycarbonyl-L-alanyl-L-prolyl-L-proline benzyl ester (6.3 g, 88.7%) having melting point of 143° to 145° C. and specific rotatory power of [α]D25 =-131.0° (C-1, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:28]3[NH:34][N:33]=[N:32][N:29]=3)([CH3:31])[CH3:30])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(CCCCCC(C)(C)C#N)oc2-c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(CCCCCC(C)(C)c3nnn[nH]3)oc2-c2ccc(OC)cc2)cc1
Yield: 50.8 %

Procedure:
5 g of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl)-2,2-dimethylheptanenitrile in 12 cm3 of dimethylformamide are treated with twice 2.7 g of sodium azide and twice 4.95 g of triethylamine hydrochloride according to the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 3.5 cm in diameter containing 120 g of silica gel (50 to 200μ). The column is eluted, collecting 50 cm3 fractions, with 0.5 liter of diisopropyl ether and then with 1.3 liters of a diisopropyl ether/ethyl acetate (70:30 by volume) mixture. The fractions emerging at between 0.85 liter and 1.3 liters are concentrated under reduced pressure (0.2 kPa). The solid is taken up with 30 cm3 of diethyl ether and drained, washed with 10 cm3 of diethyl ether and dried. 2.8 g (50%) of 5-{7-[ 4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methyl-2heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 82° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([O:13][Si:14]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])[CH2:11][OH:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Yield: 66.9 %

Procedure:
The alcohol of Step 2 (12.8 g, 29.3 mmol) was dissolved in MeOH (135 mL) and hydrogenated with 5% Rh/C at 60 psi and 60° C. for 30 hours. The filtrate was concentrated and purified by medium pressure column chromatography (silica gel, 15% ethyl acetate in hexane) to give the title compound as a white solid (8.70 g, 67% yield, mp 61°-63° C.). Anal. calcd. for C24H49NO4Si: C, 64.96; H, 11.13; N, 3.16. Found: C, 65.16; H, 11.26; N, 3.12.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1I)[OH:4].[C:14]1([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:22]1[CH:23]=[CH:24][C:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:21]1)[OH:4]
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: OC(c1ccccc1I)C(F)(F)F
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OC(c1ccccc1-n1ccc(-c2ccccc2)n1)C(F)(F)F
Temperature: 130 °C
Yield: 23.6 %

Procedure:
2,2,2-Trifluoro-1-(2-iodo-phenyl)-ethanol (0.331 g, 1.1 mmol), 3-phenyl pyrazole (0.144 g, 1.0 mmol), CuI (0.019 g, 0.1 mmol), K2CO3 (0.290 g, 2.1 mmol), (1R,2R)-N,N′-dimethyl-cyclohexane-1,2-diamine (0.028 g, 0.2 mmol) and toluene (10 ml) were taken in a 20 ml pressure tube and the mixture was heated at 130° C. (oil bath temperature) for 12 h. The mixture was diluted with ethyl acetate and washed with H2O (2×20 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to afford 2,2,2-trifluoro-1-[2-(3-phenyl-pyrazol-1-yl)-phenyl]-ethanol (75 mg).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].Cl>ClCCl.O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH:39][S:51]([CH3:50])(=[O:53])=[O:52])[NH:13]1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCNS(C)(=O)=O)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (60 mg, 0.096 mmol) prepared in Example 121a was reacted with triethylamine and methanesulfonyl chloride (13 mg, 0.11 mmol) in dichloromethane, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:16]([C:25](OC1C=CC=CC=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:34][C:35]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:17](=[N:18][C:19]=1[CH:20]([O:21][CH3:22])[O:23][CH3:24])[N:16]([C:25]([NH:34][C:35]1[CH:42]=[C:41]([O:43][CH2:44][CH2:45][O:46][CH3:47])[C:38]([C:39]#[N:40])=[CH:37][N:36]=1)=[O:26])[CH2:15][CH2:14][CH2:13]2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(N)ncc1C#N
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cc(NC(=O)N2CCCc3cc(CO[Si](C)(C)C(C)(C)C)c(C(OC)OC)nc32)ncc1C#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenyl 6-(((tert-butyldimethylsilyl)oxy)methyl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 38, 206 mg, 0.436 mmol) and 6-amino-4-(2-methoxyethoxy)nicotinonitrile (intermediate 20, 93 mg, 0.479 mmol) in THF (3 ml) at −78° C. was slowly added LHMDS (1 M in THF, 0.959 ml, 0.959 mmol). The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to room temperature. The reaction mixture was poured into sat. aq. NH4Cl and extracted twice with DCM. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 50:50) followed by reverse phase chromatography (43 g C18 cartridge, 0.1% TFA in water/acetonitrile 90:10 to 0:100) to give the title compound as an off-white solid. (UPLC-MS 3) tR 1.59 min; ESI-MS 572.3 [M+H]+.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].B1C2CCCC1CCC2.[OH:30]O.[OH-].[Na+]>C1COCC1>[CH2:18]([CH:15]1[CH2:16][CH2:17][CH:12]([CH:9]2[CH2:10][CH2:11][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:30])[CH2:7][CH2:8]2)[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: C=CCCCC1CCC(C2CCC(CCC)CC2)CC1
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCCCCO)CC2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
4′-pent-4-enyl-4-propyl-bicyclohexyl [JP10046150] (9.9 g, 36 mmol) in THF (200 ml) are cooled to 0° C. and a 0.5 M solution of 9-BBN in THF (100 ml, 50 mmol) is added dropwise. The reaction is stirred overnight at room temp., cooled to −20° C. and 30% hydrogen peroxide (12 ml, 0.11 mol) are added followed by 32% aq. sodium hydroxide (7 ml, 76 mmol). The cooling bath is removed and the reaction is stirred overnight. Water is added and the mixture is extracted three times with ethyl acetate. The combined org. layers are washed with water and brine and are dried (Na2SO4). The solvent is evaporated and the crude product is recrystalised from ethanol to give 5-(4′-propyl-bicyclohexyl-4-yl)-pentan-1-ol as colourless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7].[Li+].[OH-]>C1COCC1.CO.O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(C)c(C)s4)cn3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)nc2)sc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of ethyl [(1S)-5-(3-{[5-(4,5-dimethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-2,3-dihydro-1H-inden-1-yl]acetate (Example 260) (80 mg, 0.17 mmol) in THF (2 mL), methanol (2 mL) and water (1 mL) was added LiOH (40 mg, 1.74 mmol). The reaction mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The residue was taken up in water and acidified with a 5% aqueous solution of H3PO4, and extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give the product (67 mg, 89%). 1H NMR (400 MHz, CD2Cl2) δ 8.57 (d, 1H), 8.06 (dd, 1H), 7.09 (d, 1H), 6.85 (d, 1H), 6.80 (d, 1H), 6.71 (dd, 1H), 4.53 (t, 2H), 4.15 (t, 2H), 3.49 (qt, 1H), 2.92-2.75 (m, 2H), 2.71 (dd, 1H), 2.45-2.28 (m, 8H), 2.32-2.22 (m, 2H), 1.82-1.70 (m, 1H); LC-MS: RT=3.41 min, (M+H)+ 439.0.
Reaction SMILES: [C:1]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:53][CH3:54])[CH2:24][N:23]3[C@H:9]([C:10](=[O:52])[NH:11][C@:12]4([C:47]([O:49]CC)=[O:48])[CH2:46][C@H:13]4[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]3=[O:25])[CH2:8]2)=[CH:3][CH:2]=1.O.CO>O1CCCC1>[C:1]1([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([O:53][CH3:54])[CH2:24][N:23]3[C@H:9]([C:10](=[O:52])[NH:11][C@:12]4([C:47]([OH:49])=[O:48])[CH2:46][C@H:13]4[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][N:19]([S:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH2:20][C@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:22]3=[O:25])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](OC)(c3ccc(-c4ccccc4)cc3)C[C@H]1C(=O)N2
Agent: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-8-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,8]triazacyclopentadecine-14a-carboxylate (60 mg, 0.071 mmol) and LiOH monohydrate (34.0 mg, 1.419 mmol) in tetrahydrofuran (2 mL)/water (0.5 mL)/MeOH (1 mL) was stirred at rt for 18 h. It was then concentrated in vacuo and partitioned between water and ether. The aqueous phase was adjusted to pH=4 using 1N HCl and extracted with EtOAc. The organic phase was then dried over MgSO4, filtered, and concentrated to isolate 52 mg of the crude product as an off-white solid. Purification by preparative HPLC gave 15 mg of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-methoxy-8-(2-nitrophenylsulfonyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[n]pyrrolo[2,1-c][1,4,8]triazacyclopentadecine-14a-carboxylic acid as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].[OH-].[Na+]>O.O1CCOCC1>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([O:11][CH2:10][CH2:12][NH2:13])[CH:7]=1
Reactant: Cc1cc(C)nc(Cl)c1
Reactant: NCCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)nc(OCCN)c1

Procedure:
From 2-chloro-4,6-dimethylpyridine by treatment with ethanolamine and sodium hydroxide in a mixture of water and dioxane to afford 2-(4,6-dimethyl-pyridin-2-yloxy)-ethylamine, followed by heating with 1-fluoro-4-nitrobenzene in ethanol to give [2-(4,6-dimethyl-pyridin-2-yloxy)-ethyl]-(4-nitro-phenyl)-amine. The free amine is protected as a trifluoroacetamide by treatment with trifluoroacetic anhydride and sodium hydride in THF then the nitro group is reduced with zinc powder in the presence of ammonium chloride in ethanol. Following coupling with the appropriately-selected acid chloride, a final treatment with lithium hydroxide in methanol removes the trifluoroacetamide to give the final compound described.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33]([O-])=[O:34])[CH3:29].[K+].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCCCCC.C(OCC)(=O)C>[F:15][C:14]1[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH:7]=[CH:6][CH:5]=2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCCOC)cc3)ncc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Into a 25 ml, three neck flask under nitrogen atmosphere, a solution of N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine (0.15 g) in DMF (5 mL) was charged potassium 3-ethoxy-3-oxopropanoate (0.089 g), EDCI.HCl (0.117 g), HOBt (0.093 g) and TEA (0.164 g). The reaction mixture was stirred for 8 hr at room temperature. Completion of the reaction was monitored by TLC using hexane:ethyl acetate (5:5) as the mobile phase. After completion, the reaction mixture was poured into water. The product was extracted with ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure at 40° C. The obtained solid was purified by triturating with diethyl ether (2×10 mL) to give 0.19 g of ethyl 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-3-oxopropanoate. 1H NMR: DMSO-d6 (400 MHz): 1.182-1.234 (q, 3H, J=6.8), 3.306 (s, 3H), 3.461 (s, 2H), 3.623-3.646 (t, 2H, J=4.8), 4.010-4.033 (t, 2H, J=4.4), 4.090-4.144 (t, 2H, J=7.2), 6.775-6.797 (d, 2H, J=8.8), 7.267-7.283 (d, 2H, J=6.4), 7.511-7.533 (d, 1H, J=8), 7.575-7.591 (d, 1H, J=6.4), 7.817 (s, 1H), 8.058-8.066 (d, 1H, J=3.2), 8.963 (s, 1H), 9.375 (s, 1H), 10.162 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][C:20]([CH3:21])([CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccccc1
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)SC(C)(C)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 16.25 g (0.0575 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 13.6 g (0.115 mol α-methylstyrene in 50 ml toluene was heated at reflux for 2 hours. The reaction mixture was evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (hexane eluant) to give the product, m.p. 100°-104° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]=[CH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=2)[NH:3]1.[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][NH2:33])[CH2:27]1>C(O)C>[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH2:32][NH:33][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH:12]=[CH:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=[CH:16][CH:15]=3)[N:3]=2)[CH2:27]1
Reactant: NCC1CCCC(CN)C1
Reactant: ClC1NC(C=Cc2cccc3ccccc23)=Nc2ccccc21
Solvent: CCO
Product: NCC1CCCC(CNc2nc(C=Cc3cccc4ccccc34)nc3ccccc23)C1
Temperature: 25 °C

Procedure:
4-Chloro-2-(2-naphthalen-1-yl-vinyl)-3,4-dihydro-quinazoline (0.08 mmol), C-(3-aminomethyl-cyclohexyl)-methylamine (0.24 mmol) and 2 ml ethyl alcohol are placed in an 8 ml glass vial sealed with a teflon-lined screw cap. The mixture is heated at 80° for 3 hrs. After cooling to rt, the ethyl alcohol is removed. Ethyl acetate (3 ml) and water (3 ml) are added to the vial. After agitation, the water was removed. The procedure is repeated with water and aq. NaCl (sat.). Purification with silica gel afforded (3-aminomethyl-cyclohexylmethyl)-[2-(2-naphthalen-1-yl-vinyl)-quinazolin-4-yl]-amine;
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([O:10][CH2:11][C@H:12]2[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C@@H](C3C=CC(OC)=CC=3)[O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1COCC1.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][C@H:12]([OH:13])[C:17]([CH3:18])([CH3:19])[CH2:16][OH:15])=[O:9])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: COc1ccc([C@@H]2OCC(C)(C)[C@H](COC(=O)c3ccc([N+](=O)[O-])cc3)O2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(CO)[C@@H](O)COC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of compound obtained in Step C (4.4 g, 10.96 mmol) in THF (5 ml) and acetic acid (70%) (50 ml) was heated at 60° C. for 4 hours. The solvent was concentrated under reduced pressure and dissolved in EtOAc. The organic layer was washed with NaHCO3 and brine. The organic phase was concentrated under reduced pressure and the crude was crystallized from Et2O and n-Hexane at 0° C. to give a white solid.