Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.[C:30]([NH:40][C@H:41]([C:45]([O:47][CH:48]([CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:64])[CH2:49][O:50][C:51](=[O:57])[CH2:52][CH2:53][C:54](O)=[O:55])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:54](=[O:55])[CH2:53][CH2:52][C:51]([O:50][CH2:49][CH:48]([O:47][C:45](=[O:46])[C@H:41]([CH:42]([CH3:44])[CH3:43])[NH:40][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:58][O:59][C:60](=[O:76])[C@H:61]([CH:73]([CH3:75])[CH3:74])[NH:62][C:63]([O:65][CH2:66][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])=[O:57])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)O)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F)OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (0.538 g, 2 mmole), HOBT (0.327 g, 2.42 mmole), DMAP (29.3 mg, 0.24 mmole) and succinic acid 2,3-bis-(N-CBZ-L-valyloxy)-1-propyl ester (1.6 g, 2.42 mmole) was coevaporated two times with DMF and reduced to about 50 ml. DCC (0.536 g, 2.6 mmole) was added and the mixture was stirred 72 hours at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 100 ml of ethyl acetate was added and the organic phase washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 0.65 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1.C1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N+:3]([O-:20])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1cc2ccccc2cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: ClCCl
Product: [O-][n+]1cc2ccccc2cc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 32.6 %

Procedure:
A mixture of 3-chloroisoquinoline (18.23 g), m-chloroperbenzoic acid (36.46 g) and benzene (180 ml) was stirred at ambient temperature for a period of 2.5 days. The mixture was diluted with dichloromethane and the resultant solution was washed several times with a aqueous 5% sodium bicarbonate solution and finally with water. The organic phase was dried over anhydrous magnesium sulfate and the solvent was evaporated to give a solid residue. The solid was recrystallised from ethyl acetate to give 3-chloroisoquinoline-2-oxide (6.53 g) as colourless crystals mp 147°-151° C.
Reaction SMILES: [OH-].[K+].[CH:3]([NH:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[S:8])=O.Cl>O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]1[CH:3]=[N:5][N:6]=[C:7]1[SH:8]
Reactant: O=CNNC(=S)Nc1ccccc1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Fc1ccccc1-n1cnnc1S
Reaction time: 1 h

Procedure:
One and one-tenth grams (20 mmoles) of potassium hydroxide were dissolved in 50 ml. of water. 1-Formyl-4-(2-fluorophenyl)thiosemicarbazide, 3.5 g. (16.5 mmoles), was dissolved in the basic solution by warming on the steam bath until solution was completed. The heating was continued for one hour. The cooled reaction mixture was poured into a dilute solution of hydrochloric acid. The insoluble product was recovered from the acidic solution by filtration. The product was washed with water, collected and dried. The yield was 2.5 g. of 4-(2-fluorophenyl)-1,2,4-triazole-3-thiol, m.p. about 166°-167°C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][NH:17]1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][NH:17]1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: NN1C=CC=CN1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)NN1C=CC=CN1
Yield: 19.7 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 2-aminopyridazine as the raw materials, the same operation as the Example 198(3) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[F:12][C:13]([F:17])([F:16])[CH2:14]I>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][C:13]([F:17])([F:16])[F:12])[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: FC(F)(F)CI
Product: Fc1ccc2c(c1)c(I)nn2CC(F)(F)F
Yield: 46 %

Procedure:
The title compound was prepared in 46% yield from 5-fluoro-3-iodo-indazole and 1,1,1-trifluoro-2-iodoethane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 4.91-4.97 (2H, m), 7.17 (1H, dd, J=2.0, 8.0 Hz), 7.30 (1H, td, J=2.0, 8.4 Hz), 7.38 (1H, dd, J=3.6, 9.2 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=3)[CH:8]=2)=[N:4][N:3]=1.Cl[C:23]1C=CC=C(C(OO)=O)C=1.[S:33]([O-:37])([O-])(=[O:35])=S.[Na+].[Na+]>CN(C)C(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([S:33]([CH3:23])(=[O:37])=[O:35])=[CH:18][CH:19]=3)[CH:8]=2)=[N:4][N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(Nc2cc(-c3nnc(C)o3)ccn2)cc1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nnc(-c2ccnc(Nc3ccc(S(C)(=O)=O)cc3)c2)o1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4-(5-methyl-1,3,4-oxadiazol-2-yl)-N-[4-(methylthio)phenyl]pyridin-2-amine (441 mg, 1.48 mmol) in N,N-dimethylacetamide (5 mL) was added m-chloroperbenzoic acid (70%, 531 mg, 2.22 mmol) at room temperature, and the resulting mixture was stirred for 1 hr. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 15 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from hexane/tetrahydrofuran to give the title compound (213 mg, yield 43%) as colorless crystals.
Reaction SMILES: [CH:1]1([C@@H:7]([NH2:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]1[C:12]([CH3:14])([CH3:13])[CH2:11]1>>[CH:1]1([C@@H:7]([NH:9][CH2:11][C:12]([CH3:14])([CH3:13])[OH:10])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: C[C@H](N)C1CCCCC1
Product: C[C@H](NCC(C)(C)O)C1CCCCC1

Procedure:
(1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].CN1CCOCC1>C(#N)C>[CH3:18][C:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH2:14][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:26])=[O:27])=[CH:21][CH:20]=1)([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCc2ccccc2N1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COC(=O)C1CCc2ccccc2N1S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 18 h

Procedure:
A solution is prepared of 300 mg (1.32 mmol) of 1,2,3,4-tetrahydro-2-quinolinylcarboxylic acid methyl ester in 20 ml of acetonitrile and, at ambient temperature, 309 mg (1.32 mmol) of 4-(1,1-dimethylethyl)-benzenesulfonyl chloride are added, then 0.29 ml (2.64 mmol) of N-methylmorpholine. The reaction mixture is agitated for 18 hours with solvent reflux and then concentrated under reduced pressure. The evaporation residue is collected in 50 ml of ethyl acetate and washed with a solution of hydrochloric acid 1 N then by a solution of saturated sodium bicarbonate. The organic phase is dried on magnesium sulfate and concentrated under reduced pressure. The raw product is purified by silica gel chromatography eluting with the help of a methylcyclohexane/ethyl acetate mixture (99/1 then 95/5; v/v). In this way the expected product is obtained in the form of a white solid (yield=22%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[N:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[N:37][C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Clc1cc(Oc2cnc3ccccc3n2)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cnc5ccccc5n4)ncn3)CC1)C(=O)N2
Temperature: 90 °C
Reaction time: 8 h

Procedure:
24 mg (0.087 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 20 mg (0.077 mmol) 2-(6-chloro-pyrimidin-4-yloxy)-quinoxaline and 0.050 mL (0.29 mmol) DIPEA were combined in 1.0 mL DMF and stirred overnight at 90° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:11]2[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1>COCCOC.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2([C:24]3[CH:25]=[C:26]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([O:38][CH3:37])[CH:44]=4)[CH:27]=[CH:28][CH:29]=3)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:15][CH:11]2[CH2:10][O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC2CON(Cc3ccccc3)C2(c2cccc(Br)c2)C1
Reactant: COc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cccc(-c2cccc(C34CC(O[Si](C)(C)C(C)(C)C)CC3CON4Cc3ccccc3)c2)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-benzyl-6a-(3-bromophenyl)-5-(tert-butyldimethylsilyloxy)hexahydro-1H-cyclopenta[c]isoxazole (7.42 g, 15.2 mmol) in 1,2-dimethoxyethane (30 mL) is added 2 M aqueous solution of sodium carbonate (22.8 mL, 45.6 mmol), 3-methoxyphenylboronic acid (2.77 g, 18.2 mmol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (0.759 g, 0.911 mmol). The reaction mixture is heated at 110° C. for 7 hours. The reaction is cooled, diluted with ethyl acetate, and filtered. The resulting filtrate is separated and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 10% to 20% ethyl acetate in hexanes gradient over 20 minutes to give the title compound (7.59 g, 92%). ES/MS m/e: 516 (M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](O)=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Br:31][C:32]1[CH:33]=[C:34]([NH2:39])[C:35]([NH2:38])=[CH:36][CH:37]=1.C(O)(=O)C>C(#N)C>[Br:31][C:32]1[CH:37]=[CH:36][C:35]2[NH:38][C:5]([C@@H:4]([NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][CH2:2][CH3:1])=[N:39][C:34]=2[CH:33]=1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Br)cc1N
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Temperature: -20 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of Boc-NVA-OH (4.5 g, 21 mmol) in acetonitrile (68 mL) and 4-methylmorpholine (2.41 mL, 21.9 mmol) cooled to −20° C. was added isobutyl chloroformate (2.7 mL, 21 mmol) dropwise. The mixture was stirred for 120 minutes at −20° C. and then 4-bromo-1,2-benzenediamine (3.87 g, 20.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (20 mL, 400 mmol) and stirred at 70° C. for 6 hours. The acetic acid was removed in vacuo and the mixture was redissolved in ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was redissolved in dichloromethane, treated with activated carbon and filtered through a plug of celite. Purification by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (5.95 g, 78%) as a white solid.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[ClH:16]>O>[CH2:1]([Cl:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCO
Reactant: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCl

Procedure:
A 1 l jacketed glass reactor with a glass paddle stirrer, an immersed tube for reactant metering and an attached water separator is initially charged with 200 g of N-n-octylalkylpyridinium chloride (prepared according to Example 2) as catalyst and adjusted to a temperature of 150° C. 243 g of n-tetradecanol are introduced uniformly via the immersed tube within 4.5 h. Over the entire reaction time, gaseous hydrogen chloride in a slight excess is metered in via the immersed tube, while the water of reaction formed is removed distillatively from the reaction mixture. The performance of the reaction and workup are analogous to Example 4a. After a total reaction time of 7.5 h, the conversion based on n-tetradecanol is 99.5%.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6].CC(C)([C@@H](OCC1C=CC=CC=1)C=C)CO.[N-:49]=[N+:50]=[N-:51].[Na+]>CS(C)=O>[N:49]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:32])([CH3:31])[C@@H:11]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:12]([O:14][CH2:15][CH2:16][O:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:13])(=[O:7])=[O:6])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Agent: C=C[C@H](OCc1ccccc1)C(C)(C)CO
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)OCCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 11.0 g of a mixture of (ethoxycarbonyloxy)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (32a) and (3R)-4,4-dimethyl-3-(phenylmethoxy)-3,4,5-trihydrofuran-2-one (1) dissolved in 100 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 2.4 g (37 mmol) of sodium azide (NaN3). After work-up, the crude title compound (32b) was obtained and used in the next step without further purification. MS (ESI) m/z 524.07 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][C:30]=1C(F)(F)F)[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14]C1C=CN=CC=1.[CH2:37](O)[CH3:38]>[Pd].[C]>[F:1][C:2]([F:36])([F:35])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:30]=1)[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:37][CH:38]=1.[F:1][C:2]([F:36])([F:35])[C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:35])[F:36])[CH:30]=1)[CH2:6][O:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][NH:11][C:12](=[O:21])[CH:13]=[CH:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:37][CH:38]=1
Reactant: O=C(CCc1ccncc1)NCC(COCc1ccc(C(F)(F)F)c(C(F)(F)F)c1)c1ccccc1
Reactant: CCO
Agent: [Pd]
Product: O=C(C=Cc1cccnc1)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Product: O=C(CCc1cccnc1)NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Yield: 90 %

Procedure:
In the same manner as in the case of synthesis of Compound 48, Compound 49 (3.61 g, 90%) was produced as crystals from Compound 46 (4.00 g, 7.8 mmol), 5% Pd-carbon catalyst (0.5 g) and ethanol (100 mL).
Reaction SMILES: CS[CH2:3][CH:4]([C:14]#[N:15])[CH2:5][O:6][CH2:7][CH:8]([C:12]#[N:13])CSC.S(Cl)([Cl:19])(=O)=O.[CH2:21]([Cl:23])Cl>>[Cl:19][CH2:3][CH:4]([C:14]#[N:15])[CH2:5][O:6][CH2:7][CH:8]([C:12]#[N:13])[CH2:21][Cl:23]
Reactant: CSCC(C#N)COCC(C#N)CSC
Reactant: ClCCl
Reactant: O=S(=O)(Cl)Cl
Product: N#CC(CCl)COCC(C#N)CCl
Reaction time: 1 h

Procedure:
Methylthiomethyl 2-cyanoethylether (3.3 g, 25 mmol) was dissolved in 70 mL of methylene chloride, and 2 mL of sulfuryl chloride (25 mmol) was added dropwise, and the reaction was further performed at room temperature for 1 hour.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[O:5][CH2:4][C@@H:3]1[OH:13].C(=O)(O)[O-].[Na+].[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(OC)(C)(C)C>O1CCCC1.O>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[O:5][CH2:4][C@H:3]([OH:13])[C@H:2]2[NH:1][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N[C@H]1c2cc(Br)ccc2OC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(N[C@H]1c2cc(Br)ccc2OC[C@@H]1O)c1ccc(F)cc1
Reaction time: 2 h
Yield: 221.5 %

Procedure:
To a suspension of (3R,4S)-4-amino-6-bromo-chroman-3-ol (692 g, 2.84) and sodium bicarbonate (476 g, 5.67 mol) in tetrahydrofuran (3.0 L) and water (3.0 L) at 17° C. add 4-fluorobenzoyl chloride (369 mL, 3.12 mol) dropwise via addition funnel over 15 min. and stir for 2 hr. Add water (2 L) and methyl tert-butyl ether (3.5 L) and stir for 5 min. Separate the organic phase and wash it with water (2 L) and brine (2 L). Dry the organic portion over anhydrous magnesium sulfate and concentrate in vacuo to obtain a pale yellow solid (2.3 kg). Triturate the solid in heptane (5 L) at 25° C. for 3 h. Collect by filtration and dry in an oven at 50° C. for 12 hr. to obtain the title compound (975 g, 94%) as a white solid. LC-ES/MS m/z (79Br/81Br) 366/368 [M+H]+.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([O:52][CH3:53])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:39])[CH3:40])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)(OC)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a stirring solution of 80 mg (0.11 mmol) of 2-[3-(1-benzyl-1H-Indazol-3-ylmethyl)-3-methoxy-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 10 mL of a 10% solution of formic acid in absolute ethanol is added 70 mg of 10% palladium on carbon. The resulting black suspension is heated at reflux for 6 h, and then cooled to RT. The reaction mixture is filtered through Celite to remove the catalyst and the solvent removed in vacuo. Purification of the residue via silica gel MPLC using an Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization afforded 41 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.83 (d, 1H, J=8.3), 7.38-6.94 (m, 16H), 6.59 (d, 1H, J=7.1), 4.76 (m, 1H), 4.19 (s, br, 2H), 3.85 (d, 1H), J=15.7), 3.73 (m, 4H), 2.88 (s, 3H), 0.93 (m, 6H); low resolution MS (FAB)m/e 618 (MH+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:24][C:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:12][CH2:11][C:9]2[CH:10]=[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[NH:13][C:6]3=[N:7][CH:8]=2)[CH:22]=1)([CH3:26])[CH3:25]
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CC(C)(C)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 120 °C
Yield: 13.9 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 75 mg, 0.349 mmol), 4-chloro-6-(1,1-dimethylethyl)pyrimidine (Intermediate 10, 89 mg, 0.523 mmol) and DIPEA (0.122 mL, 0.697 mmol) were added together in N-methyl-2-pyrrolidone (2 mL) and the resulting mixture was heated at 120° C. for 2 hours and allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (17 mg);