Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15]N1C(=O)CCC1=O.[OH-].[Na+].C(OC(=O)C)C>C(#N)C>[Cl:15][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([F:12])([F:13])[F:14])[C:7]=1[NH2:8]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1c(Cl)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Yield: 97.1 %

Procedure:
4-Nitro-2-trifluoromethylaniline (15 g) and N-chlorosuccinimide (10.7 g) dissolved in acetonitril (100 ml) was heated to 150° C. for 15 minutes in a sealed microwave process vial. The reaction mixture was cooled to ambient temperature and poured into 5% sodium hydroxide (500 ml) and ethylacetate (400 ml). After seperation the organic phase was dried (MgSO4), filtered and concentrated in vacuo, followed by purification by flash chromatography to furnish 17.0 g (97% yield) of the title compound as a yellow solid. LC-MS (m/z) 240 (MH+); tR=4.76, (UV, ELSD) 97%, 96%. 1H NMR (500 MHz, DMSO-d6): 7.15 (s, 2H), 8.15 (d, 1H), 8.40 (d, 1H).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)(=O)=O.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1O)[CH:29]=[O:30]>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:5][CH:6]1[CH2:9][N:8]([C:10]([C:12]2[O:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[N:15][N:16]=2)=[O:11])[CH2:7]1)[CH:29]=[O:30]
Reactant: COc1ccc(-c2nnc(C(=O)N3CC(OS(C)(=O)=O)C3)o2)cc1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Oc4ccc(C=O)cc4Cl)C3)o2)cc1
Yield: 15 %

Procedure:
Using a similar protocol as described in Example 71A employing 73B and 3-chloro-4-hydroxybenzaldehyde as starting materials afforded 80 mg (15%) of 79A as a solid. 1H NMR (500 MHz, CDCl3): δ 3.89 (s, 3H), 4.43 (m, 1H), 4.74 (m, 1H), 4.85 (m, 1H), 5.21 (m, 2H), 6.75 (s, 1H), 7.02 (d, 2H), 7.79 (d, 1H), 7.97 (s, 1H), 8.11 (d, 2H), 9.89 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34](O)[CH2:35][CH2:36][CH2:37][CH3:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:34]([O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])/[CH:15]=[CH:14]/[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH2:19]1)=[O:25])[CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Reactant: CCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#C[C@H](CC(=O)OCCCCC)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine (0.6 g), n-pentylalcohol (0.16 ml) and N,N-dimethylaminopyridine (16 mg) in dichloromethane (6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.27 g) at 0° C. After stirring at room temperature for overnight, the solution was evaporated in vacuo. The residue was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate, water and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with AcOEt:Hexane=(1:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine n-pentyl ester as a colorless oil (0.65 g, 94.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:22])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:21])[CH3:20])[CH:12]=1)[CH:5]=[O:6].[BH4-].[Na+]>CO>[CH3:22][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH:19]([CH3:20])[CH3:21])[CH:12]=1)[CH2:5][OH:6]
Reactant: COc1ccc(Oc2c(C)cc(C=O)cc2C)cc1C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Oc2c(C)cc(CO)cc2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a stirred solution of 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzaldehyde (4.1 g, 15.2 mmol, Example 28, step a) in methanol (35 mL) at 0° C. was slowly added NaBH4 (1.16 g, 30.5 mmol). The reaction mixture was stirred at room temperature for 5 h and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2:4) to afford 3,5-dimethyl-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl alcohol as a white solid (3.4 g, 83%, m.p.: 78-80° C.): 1H NMR (300 MHz, CDCl3): δ 7.12 (s, 2 H), 6.80 (d, J=3.3 Hz, 2 H), 6.67 (d, J=9.0 Hz, 1 H), 6.36 (dd, J=3.0, 8.7 Hz, 1 H), 4.68 (s, 2 H), 3.80 (s, 3 H), 3.35-3.25 (m, 1 H), 2.16 (s, 6 H), 1.19 (d, J=7.2 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:4); Rf=0.5.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:49]([C:45]2[CH:46]=[CH:47][CH:48]=[C:43]([O:42][CH3:41])[CH:44]=2)(=[O:51])=[O:50])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.8 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., and 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 551 mg, quantitative).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:55][CH2:54][CH2:53][C@H:20]1[C:21]([NH:23][C@H:24]([C:46]([NH:48][CH2:49][C:50]([OH:52])=[O:51])=[O:47])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:45])[NH:30][S:31]([C:34]1[C:43]([CH3:44])=[C:41]([CH3:42])[C:38]([O:39][CH3:40])=[CH:37][C:35]=1[CH3:36])(=[O:33])=[O:32])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:56]1[C:60](=[O:61])[CH2:59][CH2:58][C@H:57]1[C:62](O)=[O:63]>>[NH:56]1[C:60](=[O:61])[CH2:59][CH2:58][C@H:57]1[C:62]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:17]([N:19]1[CH2:55][CH2:54][CH2:53][C@H:20]1[C:21]([NH:23][C@H:24]([C:46]([NH:48][CH2:49][C:50]([OH:52])=[O:51])=[O:47])[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[NH:45])[NH:30][S:31]([C:34]1[C:43]([CH3:44])=[C:41]([CH3:42])[C:38]([O:39][CH3:40])=[CH:37][C:35]=1[CH3:36])(=[O:33])=[O:32])=[O:22])=[O:18])[CH2:11][O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:63]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O)c(C)c1C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Product: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H]2CCC(=O)N2)C(=O)NCC(=O)O)c(C)c1C

Procedure:
The coupling and Nα -deprotection processes were repeated in the same manner to prepare H-Asn-Ser(But)-Pro-Arg(Mtr)-Gly-resin, and then the coupling process using pGlu-OH were performed to obtain pGlu-Asn-Ser(But)-Pro-Arg(Mtr)-Gly-resin. After drying, the resin was stirred in TFA-anisole (10-1 ml) for 4 hours at room temperature. The resin was removed by filtration and was washed with TFA.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[C:10]3[C:15]([CH:16]=[CH:17][C:7]=2[C:6]=1[O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:4].C1COCC1.O.[OH-].[Li+].Cl>O>[C:20]([CH2:19][O:18][C:6]1[C:7]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:8]=2[S:9][C:5]=1[C:3]([OH:4])=[O:2])([OH:22])=[O:21]
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2c1ccc1ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(C(=O)O)sc2c1ccc1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 mL round bottom flask added 3-ethoxycarbonylmethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid methyl ester (0.116 g, 0.34 mmol) and 5 mL THF. To this mixture added a solution of lithium hydroxide hydrate (0.057 g, 1.35 mmol) in 3 mL water. This mixture was allowed to stir at room temperature for 16 hours. At this time 15 mL 1.2 N HCl was added, and a precipitate formed. The solids were collected by filtration and dried in vacuo. 3-carboxymethoxy-naphtho[1,2-b]thiophene-2-carboxylic acid was isolated as a tan solid (0.096 g, 93%). 1H NMR (400 MHz, DMSO-D6) δ ppm 5.06 (s, 2H) 7.69 (m, 2H) 7.91 (d, J=8.84 Hz, 1H) 7.95 (m, 1H) 8.08 (m, 1 H) 8.19 (t, J=4.0 Hz, 1H).
Reaction SMILES: [NH:1]([CH2:3][C:4]([O-:6])=[O:5])[CH3:2].[Na+].[N:8]#[C:9][NH2:10]>O>[OH2:5].[O:5]=[C:4]([CH2:3][N:1]([C:9](=[NH:8])[NH2:10])[CH3:2])[OH:6]
Reactant: CNCC(=O)[O-]
Reactant: N#CN
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=N)N
Temperature: 50 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
462.5 g (1.67 moles) of a technical 40% by weight aqueous sodium sarcosinate solution and 200 g of water were take. A pH value of 9.81 (at 20° C.) was adjusted with concentrated 98% by weight formic acid. The reaction mixture was heated to 50° C. 138.2 g (1.65 moles) of SKW cyanamide L 500 (technical aqueous cyanamide solution with a content of 50.2% by weight) were added uniformly with vigorous stirring at an internal temperature of 50° to 52° C. over the course of 3 hours. The reaction mixture was further stirred for 1 hour at an internal temperature of 50° C. Subsequently, the reaction product was filtered off with suction and, without washing, suspended in 330 g of water. The suspension was stirred for 2 hours at 20° C. It was then filtered off with suction and the residue washed twice with 100 ml of water. After drying in a vacuum at 30° C. and 20 mbar pressure, there were obtained 165.2 g (67.1% of theory) creatine monohydrate.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([O:9]C)=[O:8])=[O:4].[OH-].[Li+].Cl>C1COCC1.O>[OH:1][C@@H:2]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:3]([NH:5][C@@H:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](O)C(=O)N[C@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2S)-{[(2S)-2-hydroxy-4-methylpentanoyl]amino}(phenyl)acetate (76a) (4.185 g) in THF (30 ml) and water (15 ml) cooled to 0° C. was added lithium hydroxide (1.45 g) portion wise. The mixture was stirred at RT overnight. The reaction was acidified with 1N hydrochloric acid until pH=1. The mixture was concentrated to remove THF and extracted with Ethyl acetate (3×). The organic layers were washed with water, brine, dried, filtered and evaporated to afford the title compound as a tacky white solid. Trituration with dichloromethane/diethyl ether yielded a free flowing solid (3.85 g). 1H NMR (300 MHz, CDCl3) δ 0.89-0.94 (m, 6H), 1.45-1.63 (m, 2H), 1.76-1.83 (m, 1H), 3.25 (bs, 2H), 4.20-4.25 (m, 1H), 5.56 (d, 1H, J=7 Hz), 7.35-7.39 (m, 5H), 7.53 (d, 1H, J=7 Hz). MS APCI, m/z=266 (M+1). LC/MS: 1.68 min.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:16])[C:14]=1[CH3:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.C(N(CC)CC)C.[CH2:24]([N:29]=[C:30]=[O:31])[CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[CH3:15][C:14]1[C:13](=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:4][NH:3][C:30]([NH:29][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:31]
Reactant: Cc1c(CN)[nH]c2ccccc2c1=O
Reactant: CCCCCN=C=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCNC(=O)NCc1[nH]c2ccccc2c(=O)c1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 2-(aminomethyl)-3-methylquinolin-4(1H)-one dihydrochloride (160 mg) in chloroform (5 mL) were sequentially added triethylamine (0.26 mL) and pentyl isocyanate (0.09 mL), and the mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 1-[(3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl]-3-pentylurea (117 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:23]=O>[Ni].CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][N:12]([CH3:23])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: COc1cc2c(cc1O)CNCC2c1ccc(Cl)c(Cl)c1
Reactant: C=O
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1O)CN(C)CC2c1ccc(Cl)c(Cl)c1

Procedure:
The free base prepared from 3.7 g. of rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-7-isoquinolinol hydrochloride is treated with 100 ml. of methanol and 5 ml. of 35% formaldehyde solution and, after standing at room temperature for 2 hours, hydrogenated with 5 g. of Raney nickel. After filtration, evaporation and acidification with ethanolic hydrogen chloride, a crystallized product is obtained. Recrystallization from methanol-ether gives rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6-methoxy-2-methyl-7-isoquinolinol hydrochloride, m.p. 253°-254°C.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:13]2[C:7]3[C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:19][C:8]=3[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:37][CH2:36]1
Reactant: O=C1Nc2ccccc2Sc2sc3ccccc3c21
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Sc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using [1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one (500 mg), phosphorus oxychloride (6.3 g), N,N-dimethylaniline (109 mg) and 1-methylpiperazine (5 ml), 12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine (278 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH2:19][CH3:20])[CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:35]1([C:46](O)=[O:47])[CH:36]=[CH:37][CH:38]=[C:39]2[CH2:45][CH2:44][CH2:43][CH:42]=[CH:41][C:40]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:46]([C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[CH2:45][CH2:44][CH2:43][CH:42]=[CH:41][C:40]=34)=[O:47])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:23]=3)=[CH:6][CH:7]=2)=[CH:13][C:14]=1[CH2:19][CH3:20]
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CCc1cc(Oc2ccc(C(O)C(N)Cc3cccc(OC(F)(F)C(F)F)c3)cc2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CCc1cc(Oc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-((4-chloro-3-ethylphenyl)oxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.60 mmol) in acetonitrile (16 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (114 mg, 0.60 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (174 mg, 0.91 mmol) and 1-hydroxy-1H-benzotriazole (92 mg, 0.60 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (318 mg, 79%).
Reaction SMILES: S(O)(O)(=O)=O.[F:6][CH:7]([F:22])[C@@:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1.[N+:23]([O-])([OH:25])=[O:24].N.O>OS(O)(=O)=O>[F:22][CH:7]([F:6])[C@@:8]1([C:15]2[CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]1
Reactant: NC1=N[C@@](c2ccccc2F)(C(F)F)COC1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: NC1=N[C@@](c2cc([N+](=O)[O-])ccc2F)(C(F)F)COC1

Procedure:
To a solution of (R)-5-difluoromethyl-5-(2-fluoro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine sulphate (127.2 g, 371.6 mmol) in conc. H2SO4 (380 mL) was added at 5-15° C. HNO3 (25.8 g, 408.8 mmol). After addition, the reaction mixture was added slowly to 12% NH3 water solution (2.6 L) at 10-20° C. The resulted suspension (pH˜8) was filtered to provide the title compound as a yellow solid: ESIMS: 290; [(M+H)+]; 1H NMR (400 MHz, CDCl3): δ 8.89 (m, 1H), 8.14 (m, 1H), 7.18 (dd, 1H), 6.10 (t, 1H), 5.65 (br s, 2H), 4.57 (dd, 1H), 4.13 (dd, 2H), 3.88 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N-Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to −20° C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H2O. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2) afforded tert-butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12].N1C=CC=CC=1.[CH2:20]([OH:29])[CH:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:29][CH2:20]/[CH:21]=[CH:22]/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: OCC=Cc1ccccc1
Reactant: COC(=O)c1ccccc1N=C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NC(=O)OC/C=C/c1ccccc1
Reaction time: 12 h
Yield: 85 %

Procedure:
A solution of methyl-2-isocyanatobenzoate (71)(1 g, 5.6 mmol) in CH2Cl2 (100 mL) was cooled to 0° C. and treated with pyridine (7 mL, 84 mmol). Cinnamyl alcohol (2.25 g, 1.68 mmol) in CH2Cl2 (150 mL) was added dropwise to the stirring solution over a period of 1 hour and the reaction mixture was allowed to stir for 12 hours, under nitrogen. The reaction mixture was washed in brine (100 mL). The aqueous phase was washed with CH2Cl2 (3×100 mL). The organic phases were combined and washed with 1N HCl (200 mL) and dried over MgSO4. Purification was achieved through flash column chromatography (80% Pet ether:EtOAc) to furnish the carbamate (72) as a colourless solid (85%). 1H NMR (250 MHz, CDCl3) δ 10.9 (br, s, 1H, NH), 8.45 (dd. 1H, J=1.0, 8.5 Hz, aromatic H), 8.01 (dd, 1H, J=1.66, 8.0 Hz, aromatic H), 7.54 (ddd, 1H, J=1.67, 7.3, 8.5 Hz, aromatic H), 7.5-7.2 (m, 5H, coc aromatic H), 7.03 (ddd, 1H, J=1.2, 8.0 Hz, aromatic H), 6.71 (d, 1H, J=16 Hz, 3′-H), 6.35 (dt, 1H, J=6.3, 16 Hz, 2′-H), 4.48 (dd, 2H, J=1.3, 6.3, 1′-H), 3.91 (s, 1H); 13C NMR (62.9 MHz, CDCl3) δ 169.0 (ester carbonyl), 153.5 (CO-carbamate), 141.9 (aromatic quat), 136.8 (aromatic quat), 135.0 (methine), 131.3 (methine), 129.0 (methine), 128.4 (methine), 127.1 (methine), 123.9 (alkenic methine), 122.0 (methine), 119.3 (methine). 114.8 (aromatic quat), 66.1 (methylene-Coc), 57.7 (OCH3). IR (neat) ν 3295, 3116, 3025, 2957, 2242, 1956, 1927, 1814, 1732, 1697, 1592, 1532, 1450, 1305, 1245, 1165, 1090, 1038, 976, 913, 856, 836, 819, 766, 743, 692 cm−1; MS m/z 311 (M+. +1), 268, 212, 188, 152, 117.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:8]([NH:18][S@@](C(C)(C)C)=O)([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[OH-].[Na+]>ClCCl.Cl>[NH2:18][C@@:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH2:9][F:10])[CH2:11][C@H:12]([OH:17])[C:13]([F:15])([F:16])[F:14]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(R)-N-((2S,4S)-2-(3-bromophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.83 g, 4.21 mmol) was dissolved in dichloromethane 37 mL and hydrogen chloride, 4.0M solution in 1,4-dioxane (5.27 ml, 21.07 mmol) was added dropwise. The reaction was stirred at room temperature for 10 min. The reaction was worked up by addition of 1N NaOH and extraction with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered and concentrated to afford (2S,4S)-4-amino-4-(3-bromophenyl)-1,1,1,5-tetrafluoropentan-2-ol that was used without further purification.