Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([NH2:8])[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18]>>[CH:9]([C@@H:5]1[CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:7][C@@H:6]1[NH:8][C:17](=[O:18])[C:16]1[CH:15]=[C:14]([O:13][CH3:12])[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=1)([CH3:11])[CH3:10].[CH:9]([C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:7][C@H:6]1[NH:8][C:17](=[O:18])[C:16]1[CH:15]=[C:14]([O:13][CH3:12])[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=1)([CH3:11])[CH3:10]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC1CCC(C(C)C)C(N)C1
Product: COc1cc(C(=O)N[C@@H]2C[C@@H](C)CC[C@@H]2C(C)C)cc(OC)c1OC
Product: COc1cc(C(=O)N[C@H]2C[C@H](C)CC[C@H]2C(C)C)cc(OC)c1OC

Procedure:
The aforementioned product is obtained as a colorless solid containing in total 92.2% of the desired neomenthylamine derivatives from racemic neomenthylamine, as in the GP, by reaction with 3,4,5-trimethoxybenzoylchloride. Furthermore, two further isomeric menthylamine derivatives are present at 3.8% and 4.0%, corresponding to a purity over all stereoisomers of 100.0%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)([OH:3])=[O:2].[CH3:21][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH3:21][O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:14]3=[C:15]([C:17](=[O:20])[CH:18]=[CH:19][N:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]2=3)[CH:16]=1)=[O:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Reaction time: 1.5 h
Yield: 48 %

Procedure:
2-carboxy-4H-pyrido[3,2,1-jk]carbazole-4-one (500 mg) produced in Example 175 was suspended in tetrahydrofuran (100 ml), and methanol (several drops) was added to the suspension. Trimethylsilyldiazomethane (2M hexane solution, 1 ml) was added dropwise at room temperature, and the mixture was stirred for 90 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (250 mg, 48%).
Reaction SMILES: [C:1]1([CH:7]2[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:7]([O:11][CH2:10][CH2:9][Br:12])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2OCCO2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(OCCBr)c1ccccc1

Procedure:
A mixture of 120.14 grams (0.80 mol) of 2-phenyl-1,3-dioxolane, 142.39 grams (0.80 mol) of N-bromosuccinimide, 1 liter of carbon tetrachloride and a catalytic amount of benzoyl peroxide was heated with stirring at reflux for 5.25 hours and then cooled. The mixture was filtered, and the filtrate was concentrated to an oil. Distillation of this oil gave 147.8 grams; (80.65% of theory) of the product; bp=104°-111° C./0.40 mm.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[Cl:15])O1.Cl[C:18]1[N:23]=[C:22]([NH2:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][CH:19]=1>>[Cl:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:18]1[CH:19]=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH2:24])[N:23]=1
Reactant: CC1(C)OB(c2ccncc2Cl)OC1(C)C
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Product: Nc1nc(-c2ccncc2Cl)ccc1[N+](=O)[O-]
Yield: 99 %

Procedure:
Following the same procedure as in Intermediate 1 (step a), but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-chloropyridine, 6-chloro-3-nitropyridin-2-amine was transformed into the title compound as a white solid (2.14 g, 99%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9](Cl)[N:8]=[C:7]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:6]=1>CO>[NH2:4][C:5]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:6]=1
Reactant: C[O-]
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC

Procedure:
6.55 g of sodium methylate were added at room temperature to a solution of 4-amino-6-chloro-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 200 ml of methanol and the solution was subsequently heated at reflux for 32 hours. The methanol was removed on a rotary evaporator, the residue was taken up in methylene chloride and washed with 1N hydrochloric acid. The organic phase was dried over magnesium sulphate, the solvent was finally removed in a water-jet vacuum. The crude product was chromatographed on silica gel with methylene chloride/ methanol (10/1) as the eluent. 4-Amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine was obtained as a lemon-yellow powder MS: 325 (M).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:14][CH2:13]1.[C:32]([N:51]1[CH:55]=[C:54](B(O)O)[CH:53]=[N:52]1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[C:32]([N:51]1[CH:55]=[C:54]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][CH:6]=[C:5]3[N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([C:28]([F:29])([F:31])[F:30])(=[O:26])=[O:27])=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)[CH:53]=[N:52]1)([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: OB(O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(Br)cc34)CC2)cc1)C(F)(F)F
Product: O=S(=O)(c1ccc(OC2CCN(c3ccnc4ccc(-c5cnn(C(c6ccccc6)(c6ccccc6)c6ccccc6)c5)cc34)CC2)cc1)C(F)(F)F
Yield: 94.6 %

Procedure:
150 mg 6-bromo-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline (compound in Production Example 456) and 134 mg 1-trityl-1H-4-pyrazolylboronic acid were reacted in the same manner as in Example 9, to give 205 mg 6-(1-trityl-1H-pyrazol-4-yl)-4-[4-(4-trifluoromethylsulfonylphenoxy)piperidin-1-yl] quinoline. This product was reacted in the same manner as in Example 67, to give 90 mg of the title compound as pale yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH:27]1[C@H:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:30][C@@H:29]2[CH2:42][CH2:43][CH2:44][C@H:28]12>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:27]2[C@H:31]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:30][C@@H:29]3[CH2:42][CH2:43][CH2:44][C@H:28]23)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)=[N:4][NH2:5].[CH2:16]([N:22]1[C:26](=[O:27])[CH:25]=[CH:24][C:23]1=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH2:16]([N:22]1[C:23](=[O:28])[CH:24]2[CH:25]([N:5]=[N:4][C:3]2([CH:2]([CH3:15])[CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:26]1=[O:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(C)C(=NN)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCN1C(=O)C=CC1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCCCCCN1C(=O)C2N=NC(c3cccc([N+](=O)[O-])c3)(C(C)C)C2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-Methyl-1-(3-nitrophenyl)-1-propanone hydrazone (Preparation 57, 0.52 g, 2.5 mmol) was dissolved in dioxan (10 ml) and manganese dioxide (grade CMD-1 from Sumitomo, 5.2 g, 60.0 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 20 minutes. This solution was filtered over a pad of Celite® dropwise, directly into a solution of 1-hexyl-1H-pyrrole-2,5-dione (Preparation 56, 0.54 g, 3.0 mmol) in dioxan (10 ml). The Celite® pad was washed with dioxan (40 ml) to ensure complete addition of the reactants and then the reaction mixture was stoppered and stirred for 72 h. The reaction mixture was purified by chromatography using a Biotage Flash 40S™ cartridge packed with silica gel (40 g), eluting with petroleum ether:ethyl acetate (4:1). The title compound was obtained as a yellow solid (0.65 g, 67%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH2:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:24][C:25]([F:39])([F:38])[CH2:26][CH2:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:23])[C@@H:9]([NH:22][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([O:28][CH2:27][CH2:26][C:25]([F:39])([F:38])[F:24])=[CH:30][CH:31]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:19])[F:20])=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(OC(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethoxy)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.C1COCC1.CO.[BH4-].[Na+].Cl>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(C(=O)c3cccc(F)c3)nc3ccccc23)n[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(O)c3cccc(F)c3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
To (3-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 1 (0.15 g, 0.43 mmol) in 1:1 THF/MeOH (4 mL) at 0° C. was added sodium borohydride (0.02 g, 0.58 mmol) and the mixture was stirred at 0° C. for 30 min. To the mixture were added 6 N HCl and DMSO (3 mL), and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column eluting with gradient of solvent B=0.05% HOAC/MeOH and solvent A=0.05% HOAc/H2O) to afford (3-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanol (50 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 2.26 (s, 3H) 5.7 (s, 1H) 5.93 (s,1H) 6.44 (s, 1H) 7.07 (m, 1H) 7.34-7.39 (m, 3H) 7.54 (m, 1H) 7.81 (s, 2H) 8.59 (d, 1H) 10.42 (s, 1H) 12.15 (s, 1H); LC-MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: [CH2:1]1[N:10]2[C@H:11]3[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@H:12]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][CH2:2]1.[OH-].[K+]>C(O)CCC>[CH2:1]1[N:10]2[C@H:11]3[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]3[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3][CH2:2]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCN2
Temperature: 199 °C
Yield: 87.7 %

Procedure:
To ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (4.10 g, 14.3 mmol) was added n-butanol (18.0 mL) and KOH powder (3.0 g). The reaction was heated at 199° C. in a sealed tube for 18 hr. The solvent was removed under reduced pressure. To the residue was added water (30 mL) extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford the title compound as a pale yellow oil (2.70 g, 78%). MS-ESI: 216 [MH]+
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2].[CH3:11][SiH:12]([CH3:14])[Cl:13].[Al+3].[Cl-].[Cl-].[Cl-]>CCCCC>[CH2:1]([C:3]([Si:12]([CH3:14])([CH3:11])[Cl:13])([CH2:9][CH3:10])[CH:4]([CH2:7][CH3:8])[CH2:5][CH3:6])[CH3:2]
Reactant: CCC(CC)=C(CC)CC
Reactant: C[SiH](C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCC
Product: CCC(CC)C(CC)(CC)[Si](C)(C)Cl
Reaction time: 2 h

Procedure:
2.1 g of tetraethylethylene, 2 ml (18 mmol) of dimethylchlorosilane and 200 mg of AlCl3 are reacted according to Example 1. After 2 hours, the reaction mixture is diluted with pentane and the precipitate is filtered off. The pentane is stripped from the filtrate in vacuo and the residue is distilled. This gives 2.8 g (80% of theory) of product as a colourless liquid. Boiling point=75°-80° C./0.195 mbar.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH:3]=1.C([O-])(=O)C.[Na+].[I:30]Cl>C(O)(=O)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[C:3]=1[I:30]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)c(I)c(N)c2F)c1F
Temperature: 80 °C
Yield: 42.3 %

Procedure:
Propan-2-yl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (600 mg, 1.682 mmol) was dissolved in acetic acid (5.6 mL). Sodium acetate (1.5 g, 18.50 mmol) was added followed by iodine monochloride (2.2 g, 13.45 mmol). An exotherm of approximately 10° C. was observed during the addition. The reaction mixture was heated at 80° C. for 20 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with water, satd aq NaHCO3 solution, dried (MgSO4) and then concentrated to dryness. The residue was applied to a silica gel column (80 g) then eluted (0-70% acetone-hexanes gradient) to give an orange solid (343 mg, 42%): mp 134-135° C.; 1H NMR (400 MHz, acetone-d6) δ 7.41 (dd, J=8.5, 1.6 Hz, 1H), 7.33 (dd, J=8.5, 6.8 Hz, 1H), 6.29 (s, 2H), 5.29-5.14 (septet, 1H), 3.98 (d, J=1.1 Hz, 3H), 1.37 (d, J=6.3 Hz, 6H); EIMS m/z 396.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:7][C@@H:8]([CH2:11][CH3:12])[CH2:9][NH:10][C:22](=[O:27])[C:23]([O:25][CH3:26])=[O:24])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(=O)Cl
Reactant: CC[C@@H](CN)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC[C@@H](CNC(=O)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To an ice cold solution of (S)-tert-butyl(1-aminobutan-2-yl)carbamate (1.0 g, 5.4 mmol) and triethylamine (0.78 mL, 5.6 mmol) in DCM (33 mL) was added methyl chlorooxoacetate (0.52 mL, 5.6 mmol) dropwise. Following the addition, the reaction was allowed to warm to rt and stirred overnight. Brine was added, the layers were separated, and the aqueous layer was washed with DCM. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide a yellow oil (1.4 g, 96%), which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 7.78 (s, 1H), 4.59 (d, J=7.6 Hz, 1H), 3.92-3.81 (m, 3H), 3.69 (s, 1H) 3.45 (dt, J=13.5, 4.2 Hz, 1H), 3.39-3.22 (m, 1H), 1.47-1.38 (m, 11H), 0.98 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:6]3[C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and 4-benzyloxyphenyl isocyanate (68 mg, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as a yellow solid after column chromatography with hexane-EtOAc.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>CO>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([CH3:16])[N:12]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-c1nc(C)no1
Solvent: CO
Product: COc1cc(NC(N)=S)ccc1-c1nc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Step I (2): Methanolic ammonia (3.33 mL, 23.3 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1,2,4-oxadiazole (1.28 g, 5.18 mmol) in MeOH (12 mL). After stirring at rt for 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)thiourea (1.368 g, 5.18 mmol, 100% yield). LC-MS (M+H)+ 265.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.94 (d, J=8.56 Hz, 1 H) 7.77 (d, J=2.01 Hz, 1 H) 7.06 (dd, J=8.31, 2.01 Hz, 1 H) 3.95 (s, 3 H) 2.40 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][NH2:25]>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:25][CH3:24])[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: CN
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: CNc1nc(N)nc(-c2ccco2)c1[N+](=O)[O-]

Procedure:
From trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and methylamine in DME. ES-MS m/e(%): 236 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[C:12]([CH2:26][O:27][CH3:28])=[N:11][C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[C:48]([O:52][C:53](=[O:57])[C@@H:54]([CH3:56])[NH2:55])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl>[C:48]([O:52][C:53](=[O:57])[C@H:54]([NH:55][C:29]([C:10]1[N:11]=[C:12]([CH2:26][O:27][CH3:28])[C:13]2[C:18]([C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:17][CH:16]=[C:15]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:14]=2)=[O:30])[CH3:56])([CH3:51])([CH3:50])[CH3:49]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: COCc1nc(C(=O)O)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C(=O)N[C@H](C)C(=O)OC(C)(C)C)c(OCc2ccccc2)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a mixture of 4-Benzyloxy-1-methoxymethyl-7-phenoxy-isoquinoline-3-carboxylic acid (79 mg, 0.19 mmol), NEt3 (56 μl, 0.4 mmol), and CH2Cl2 (5 ml) cooled with an ice bath was added ClCO2iBu (26.5 μl, 0.2 mmol) with stirring. After stirring for 15 min (R)-alanine tert-butyl ester hydrochloride (36 mg, 0.2 mmol) was added and the mixture was allowed to warm up to ambient temperature overnight with stirring. Subsequently; the mixture was concentrated in vacuo. To the residue was added water (10 ml) and a few drops of aqueous 6N HCl. The mixture was extracted with EtOAc (2×15 ml). The organic phase was dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography on silica gel using EtOAc as the eluent gave the title compound as a tan oil (88 mg); MS-(+)-ion: M+23=565.2.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:24])[NH:11]2
Reactant: CCO
Reactant: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To the suspension of 4-biphenyl-2-yl-1H-indole (1.18 g, 4.4 mmol) in t-BuOH: ethanol: acetic acid (28 mL: 17 mL: 9 mL) was added pyridinium tribromide (4.39 g, 13.7 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (22 mL). Zinc dust (1.63 g, 25 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 0.93 g (74%) of 4-biphenyl-2-yl-1,3-dihydro-indol-2-one.