Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH2:13][OH:14])[O:10][CH:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H-].[Na+].Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C(COC)OC>[CH2:9]([NH:8][CH2:12][CH:11]([OH:10])[CH2:13][O:14][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Clc1ncccn1
Reactant: OCC1CN(Cc2ccccc2)C(c2ccccc2)O1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: OC(CNCc1ccccc1)COc1ncccn1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A solution of 26.93 g of 3-benzyl-5-hydroxymethyl-2-phenyl-oxazolidine in 100 ml of dimethoxyethane is added dropwise to a suspension of 2.4 g of sodium hydride in 50 ml of dimethoxyethane, whilst keeping the temperature of the reaction mixing at 20° C. The mixture is then stirred for 7 hours, after which a solution of 11.45 g of 2-chloro-pyrimidine in 30 ml of dimethoxyethane is added dropwise at 20° C. After stirring for 20 hours and boiling under reflux, the solvent is distilled off under reduced pressure, the residue is warmed with 10 ml of concentrated hydrochloric acid and 30 ml of water to 60° C. and then cooled, and the mixture is extracted with ether. 15 ml of 10 N sodium hydroxide solution are added to the aqueous phase at 0° C., the mixture is then extracted with ethyl acetate and the organic phase is dried over sodium sulphate, filtered and evaporated in vacuo. The residue is dissolved in acetone and a solution of 9.0 g of oxalic acid in acetone is added. The hydrogen-oxalate of 1-benzylamino-3-(2-pyrimidinyloxy)-2-propanol, of melting point 188°-189° C., is obtained. From this, the free base is obtained as an oil by adding sodium hydroxide solution at 0° C., extracting with ethyl acetate, drying the organic phase over sodium sulphate, filtering and evaporating.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([C:6]2([NH:8][CH2:9][C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][N:3]=[CH:2][NH:7]2)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Clc1nccc(NCc2cccs2)n1
Product: CC(C)c1ccc(C2(NCc3cccs3)C=CN=CN2)cc1

Procedure:
[2-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine (142 mg) was obtained by following general procedure Q1 from (2-chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl-amine (130 mg, 0.58 mmol) and 4-isopropylphenylboronic acid (140 mg, 0.86 mmol). LCMS m/z: 311 (M+1)+. [4-(4-Isopropyl-phenyl)-pyrimidin-4-yl]-thiophen-2-ylmethyl-amine was obtained by following general procedure Q1 from (4-Chloro-pyrimidin-2-yl)-thiophen-2-ylmethyl-amine and 4-isopropylphenylboronic acid.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[OH:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:45]I>C1COCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[CH:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[O:27][CH3:45])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cc1cc(C(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cc(C)c(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of (2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-methyl-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (8 mg, 0.01 mmol) in THF (0.15 mL) at 0° C. was added sodium hydride (4.2 mg, 0.11 mmol). The mixture was stirred at room temperature for 30 minutes. Methyl iodide (10 μL, 0.2 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The mixture was quenched with methanol and purified by chromatography over 12+S Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound (3.6 mg, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.20 (m, 6H) 1.41-1.51 (m, 1H) 1.61 (d, J=8.71 Hz, 2H) 1.67-1.74 (m, 1H) 1.93 (d, J=11.62 Hz, 1H) 2.46 (s, 3H) 3.04 (s, 3H) 4.04 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.63-4.72 (m, 3H) 4.84 (d, J=16.18 Hz, 1H) 7.27 (s, 1H) 7.30 (s, 1H) 7.63 (s, 2H) 7.77 (s, 1H). MS (ES30) Calc: 623.2, Found: 624.6 (M+1) According to the procedure described in example 23 and using the corresponding aryl bromide and aldehyde reagent, example 24 was prepared.
Reaction SMILES: [C:1]([O:4]O)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[CH:11]12[CH2:21][CH:17](C(=O)C1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1>C(O)(=O)C.ClCCl>[CH:11]12[CH2:21][CH:17]([O:4][C:1](=[O:3])[CH2:2]1)[CH:16]1[CH:12]2[CH2:13][CH2:14][CH2:15]1
Reactant: CC(=O)OO
Reactant: O=C1CC2CC1C1CCCC21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1CC2CC(O1)C1CCCC21
Reaction time: 48 h

Procedure:
18 g of a 50 % peracetic acid solution in acetic acid containing 1 g of sodium acetate were added to a stirred mixture of 15 g of tricyclo[5.2.1.02,6 ]decane-8-one (which can be purchased from Ruhrchemie, Bruchstrasse, D-42 Oberhausen Holten, West Germany) and 9 g of anhydrous sodium acetate in 60 g of dichloromethane. The temperature of the reaction mixture was kept at 20°-25° by external cooling by means of a ice-water bath during the whole addition, then it was kept at this value during 48 hours while stirring.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([NH:23][CH3:24])=[O:22])=[O:18])[CH2:13][CH2:12]3)[CH:3]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CNC(=O)COC(=O)N1CCN(CCCc2cccc(Br)c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNC(=O)COC(=O)N1CCN(CCCc2cccc(-c3cccc(Cl)c3)c2)CC1
Temperature: 150 °C
Yield: 51.4 %

Procedure:
A suspension of 0.14 g (0.35 mmol) of 2-(methylamino)-2-oxoethyl 4-[3-(3-bromophenyl)propyl]piperazine-1-carboxylate, prepared in step 7.2., in a mixture of 4 ml of toluene and 0.6 ml of ethanol is admixed with 0.08 g (0.07 mol) of the tetrakis(triphenylphosphine)palladium complex, 1.05 ml (2.1 mmol) of a 2M aqueous solution of sodium carbonate and 0.22 g (1.4 mmol) of 3-chlorobenzeneboronic acid. The mixture is heated to 150° C. under microwave irradiation for 5 minutes and the organic phase is recovered by filtration on a cartridge equipped with a frit and containing celite and sodium sulphate. The cartridge is rinsed with toluene and the filtrate is concentrated under reduced pressure. The product is purified by chromatography on silica gel, eluting with a 90/10 mixture of ethyl acetate and methanol. The eluate is subsequently taken up in n-heptane, to give 0.086 g (0.18 mmol) of product in the form of white crystals.
Reaction SMILES: Cl[C:2](=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)[CH:3]([Cl:12])[S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].CN([CH:36]=[O:37])C.C[O-].[Na+]>CO.O>[Cl:12][CH:3]([S:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[C:2]([O:37][CH3:36])=[C:13]1[C@:30]2([CH3:31])[C@H:16]([C@H:17]3[C:27](=[CH:28][CH2:29]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Reactant: CN(C)C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
20,21-Dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VII, Example 2, 1.0 g), dry DMF (20 ml) and methanol (4 ml) are stirred under nitrogen and cooled to -25°. Sodium methoxide in methanol (25%, 1 ml) is added dropwise. After 30 minutes, the mixture is quenched with water (0.33 ml) and allowed to warm to 20°-25°. The product is isolated by diluting the mixture with water and extracting with ethyl acetate. The organic layer is separated and dried over sodium sulfate and then concentrated under reduced pressure to give the title compound: NMR (CDCl3) 0.85, 0.87, 0.98, 1.36, 1.34, 3.89, 3.84, 5.03, 5.10, 5.23, 5.43, 5.53, 5.72, 5.75 and 7.4-8.0δ.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:11])[CH3:10]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:11][CH2:9][CH3:10])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCO
Product: CCOc1cncc(Br)c1
Yield: 69 %

Procedure:
Ethanol and 3,5-dibromopyridine were processed as described in Example 7A to provide the title compound (69% yield). MS (DCI/NH3) m/z 202/204 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1cccc(-c2oc(C)nc2C(=O)O)c1
Product: COc1cccc(-c2oc(C)nc2C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-methoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.01 min; [M+H]+=421.41.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)#[N:4].[Cl:14][CH2:15][CH2:16][CH:17](OS(C)(=O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[Cl:14][CH2:15][CH2:16][CH:17]([N:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:5]([C:3]#[N:4])[C:6]=2[CH:7]=[N:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Reactant: N#Cc1cccc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cccc2c1cnn2C(CCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
Sodium hydride (0.092 g, 60% in oil) was added to a solution of 4-cyanoindazole (0.300 g) in N-methylpyrrolidinone (5 mL) and the reaction mixture was stirred at room temperature for 30 minutes. Methanesulfonic acid 3-chloro-1-phenyl-propyl ester (0.573 g) was added followed by 3 ml more of N-methylpyrrolidinone. The reaction mixture was stirred for an additional 6 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water, then with brine, and dried (MgSO4). Evaporation to dryness gave a residue which was purified by column chromatography on silica gel using ethyl acetate-hexane (1:9) to give 1-(3-chloro-1-phenyl-propyl)-1H-indazole-4-carbonitrile (0.228 g) as a foam, (M+H=297).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])([F:21])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:21][C:18]1([CH2:22][N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCNCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (30 ml) was added to a solution of 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester (23 g) in dichloromethane (250 ml), and the mixture was stirred at room temperature for 5 hours. The obtained solution was concentrated, and the residue was recrystallized from ether to obtain a trifluoroacetic acid salt of 2-(4-fluoro-piperidin-4-ylmethyl)-isoindole-1,3-dione.
Reaction SMILES: [CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[S:35][CH:36]=1)\[C:29](O)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>>[CH:1]([O:14][C:15]([C@H:17]([O:26]/[N:27]=[C:28](/[C:32]1[N:33]=[C:34]([NH:37][C:38]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[S:35][CH:36]=1)\[C:29]([NH:57][CH:58]1[C:79](=[O:80])[N:60]2[C:61]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)=[O:68])=[C:62]([CH2:65][Cl:66])[CH2:63][S:64][C@H:59]12)=[O:30])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:16])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N)C(=O)N23)cc1
Reactant: O=C(O)/C(=N\O[C@@H](C(=O)OC(c1ccccc1)c1ccccc1)c1ccc(O)c(O)c1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(O)c(O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 100.7 %

Procedure:
By using 4.57 g (6 mmol) of (Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(2-tritylaminothiazol-4-yl)acetic acid, 2.03 g (5 mmol) of p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate, 1.39 ml (10 mmol) and 0.84 ml (6 mmol) of triethylamine and 0.75 ml (8 mmol) of phosphorus oxychloride, the treatment was conducted in the same manner as in Example 1 (A) to obtain 5.60 g (yield: 56%) of p-methoxybenzyl 7-[(Z)-2-[[(R)-α-benzhydryloxycarbonyl-3,4-dihydroxybenzyl]oxyimino]-2-(tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylate as a foam-like solid.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C:10]2[CH:21]=[C:22](Cl)[CH:23]=[CH:24][C:9]1=2.F[C:41](F)(F)[C:42]1C=C(C=C(C(F)(F)F)[CH:69]=1)CNC1C2C=CC3CCCC=3C=2N(C(OC(C)C)=O)CCC1>>[CH:18]([O:17][C:15]([N:11]1[C:10]2[C:21]3[CH2:41][CH2:42][CH2:69][C:22]=3[CH:23]=[CH:24][C:9]=2[CH:8]([N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:39])([F:38])[F:1])[CH:33]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:31]=2)[C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH2:14][CH2:13][CH2:12]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc3c(c21)CCC3
Reactant: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc3c(c21)CCC3

Procedure:
The titled compound was prepared in a manner analogous to the procedure for the preparation of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-(1H-tetrazol-5-yl)-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 46, from Step 2 to Step 3) by replacing (+/−)-isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with (+/−)-isopropyl 6-(3,5-bis-trifluoromethyl-benzylamino]-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylate (prepared above) in Example 46 Step 2. MS (ES−): 581 (M−H).
Reaction SMILES: I[CH2:2][C@@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C-:11]#[N:12].[Na+]>CS(C)=O>[C:11]([CH2:2][CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:12]
Reactant: CCOC(=O)C[C@H](O)CI
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(O)CC#N

Procedure:
The recombinant E. coli HB101(pNTS1G) obtained in Example 10 was inoculated in 100 ml of a 2×YT medium sterilized in a 500 ml Sakaguchi flask, and cultured with agitation at 37° C. for 13 hours. Glucose, 0.5 g, 3.2 mg of NADP, and then 0.5 g of ethyl 4-iodoacetoacetate were added to 50 ml of the resultant culture. The culture was stirred at 30° C. while being adjusted at pH 6.5 with a 5 M sodium hydroxide solution to allow for reaction for 72 hours. After the reaction, the reaction solution was subjected to extraction using ethyl acetate, the solvent was removed under decompression, and the concentrate was purified by silica gel column chromatography, to obtain 900 mg of ethyl (S)-4-iodo-3-hydroxybutyrate. The optical purity of the ethyl (S)-4-iodo-3-hydroxybutyrate was analyzed as follows and found to be 91.6% e.e. That is, the sample was heated together with sodium cyanide in dimethyl sulfoxide to obtain ethyl 4-cyano-3-hydroxybutyrate, which was then changed to a benzoic ester using benzoyl chloride under the presence of pyridine. The optical purity of the benzoic ester was measured by an HPLC method. NMR(CDC13)δ(ppm): 1.28(3H,t), 2.65(2H,d), 3.31(3H,m), 4.00(1H,m), 4.20(2H,q); Column: Chiralpak AS (0.46×25 cm) manufactured by Daicel Chemical Industries, Co., Ltd.; Column temperature: 25° C.; Eluent: n-hexane/ethanol of 95/5; Flow rate: 1 ml/min.; Detection: 254 nm; Elution time: 19.6 minutes for (S), 21.3 minutes for (R).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH2:43])[CH:38]=[CH:39][C:40]=1[Cl:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(Cl)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.564 g, 1.25 mmol), [(3-bromo-4-chlorophenyl)methyl]amine (0.275 g, 1.25 mmol, HBTU (0.474 g, 1.25 mmol), and TEA (0.348 mL, 2.5 mmol) were combined in CH2Cl2 (30 mL). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Residue taken up in EtOAc, washed with 1 N NaOH, brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. It was purified further using CombiFlash on a 40 g column eluted with 0-10% MeOH/CH2Cl2 to give the title compound as a white solid. LC-MS m/z 652.9 (M+H)+, 1.91 min (ret time); mp 115-117° C.; analytical HPLC shows 98.4% purity, (ret time 13.689 min).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:33][C:34]([NH2:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([CH2:39][NH2:40])[OH:38]>>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([C:28](=[O:29])[NH:40][CH2:39][CH2:37][OH:38])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:33][C:34]([NH2:36])=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reactant: NCCO
Product: NC(=O)Cc1cnc(Nc2ccc(N3CCC(C(=O)NCCO)CC3)cc2)cc1NCc1ccccc1
Yield: 97 %

Procedure:
20 mg of 4-(benzylamino)-6-{[4-(4-ethoxycarbonylpiperidino)phenyl]amino}pyridine-3-carboxyamide (Example 175) and 50 mg of ethanolamine were stirred at 150° C. for 2 hours. After cooling, the reaction mixture was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 20 mg (89%) of the title compound as a slight yellow crystalline powder.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].C(=O)([O-])[O-].[K+].[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:28])[C:19]([CH3:27])([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH3:20])=[CH:14][CH:13]=1>CC(N(C)C)=O>[SH:3][CH2:2][CH2:1][S:4][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:28])[C:19]([CH3:20])([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH3:27])=[CH:16][CH:17]=1
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Reactant: SCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCS)cc1)N1CCOCC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
22.5 g (0.24 mol) of 1,2-ethanedithiol are dissolved in 70 ml of dry dimethylacetamide, 10.0 g of potassium carbonate are added and the solution is heated to about 40° C. 10.1 g o(0.04 mol) of 1-(4-fluorophenyl)-2-methyl-2-morpholine-4-yl-propane-1-one (prepared as described in example 1b) in 30 ml of dry dimethylacetamide are added dropwise. The suspension is stirred for 5 h, then the solid is filtered off and washed with toluene. From the filtrate the excess 1,2-ethanedithiol and toluene are distilled off. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (20:80) as eluent. The resulting product has a melting point of 92-93° C. The structure is confirmed by the 1H-NMR-spectrum, measured in CDCl3. The signals (δ in ppm) are 1.31 (s,6H), 1.75 (t, 1H), 2.57 (t,4H), 2.80 (q,2H), 3.21 (t,2H), 3.70 (t,4H), 7.29 (d,2H), 8.51 (d,2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([OH:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([O:11][CH3:23])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(O)c3cc(Br)cnc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(OC)c3cc(Br)cnc32)cc1
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
5-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-ol (0.200 g, 0.599 mmol) was dissolved in DMF. Sodium hydride (0.0287 g, 0.718 mmol) was added and stirred for 10 minutes. Methyl iodide (0.0448 mL, 0.718 mmol) was added, and the reaction mixture was stirred overnight. The solution was partitioned between water and EtOAc. The organic layer was washed with water (3×), brine, dried over Na2SO4 and concentrated to an oil, which was purified by column chromatography (2:1 hexanes/EtOAc) to give 5-bromo-3-methoxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine (0.11 g, 52.3%) as an oil.