Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:13]([O-])=O)=[C:4]([Cl:12])[CH:5]=[C:6]([F:11])[C:7]=1[O:8][CH2:9][CH3:10].Cl.Cl[Sn]Cl.O>C(O)C>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[C:6]([F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: CCOc1c(F)cc(Cl)c([N+](=O)[O-])c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOc1c(F)cc(Cl)c(N)c1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a solution of 30-4 (22.9 g, 77 mmol) in ethanol (100 mL) at room temperature was added concentrated HCl (74 mL) and SnCl2 (44 g, 231 mmol). The mixture was allowed to stir at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×150 mL), the organic layer was combined and was concentrated under vacuum to get a crude product which was purified on silica gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 30-5 (16 g, 78%) as a white solid. LRMS: calc 266.9 and found: 267.9 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[O:10]=[C:11]([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14].N1CCCCC1>C1C=CC=CC=1>[C:11](/[C:12](=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)/[C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)/C(=C\c1ccc(F)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 4-fluorobenzaldehyde (25.5 g, 0.220 mol), methyl 3-oxobutanoate (21.80 g, 0.220 mol), and piperidine (1.0 mL) in anhydrous benzene (250 mL) was stirred for 10 minutes at room temperature and subsequently refluxed overnight in a Dean-Stark apparatus. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo to afford methyl (2Z)-2-acetyl-3-(4-fluorophenyl)-2-propenoate as a black solid (48.6 g, 99%), which was used for next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCCc1cc(NC(=S)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 55 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([NH:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)[CH2:21][C@@H:20]([C:29](=[O:49])[N:30]([CH:46]4[CH2:48][CH2:47]4)[CH2:31][C:32]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:50](Cl)(=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52]>CC#N>[CH:46]1([N:30]([CH2:31][C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)[C:29]([C@@H:20]2[CH2:21][C@H:22]([N:24]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[C:50](=[O:55])[C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:23][NH:18][CH2:19]2)=[O:49])[CH2:47][CH2:48]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCC3CC3)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](N(CC3CC3)C(=O)C(C)(C)C)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example ??? using (3R,5S)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-(cyclopropylmethyl-amino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester and pivaloylchloride. MS: 523 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.24 min.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH:7](O)[CH2:6]1>C(OC(=O)C)(=O)C>[N+:1]([O:4][CH:7]1[CH2:8][CH2:9][CH2:10][O:5][CH2:6]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: OC1CCCOC1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])OC1CCCOC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a reaction vessel was placed 50 ml acetic anhydride. While cooling, 14 ml of 90 percent fuming nitric acid was added. Following this, 25 g of tetrahydro-2H-pyran-3-ol was added dropwise at -8° to -10° C. over a one hour period. Stirring was continued for 1.5 hours at -10° C. The mixture was then allowed to warm to room temperature and then poured into an ice-water mixture. The organic phase settled and was separated. The organic phase was diluted with methylene chloride and also washed with aqueous NaHCO3 and dried over MgSO4. The solvent was removed under vacuum leaving 24.04 g of tetrahydro-2H-pyran-3-ol nitrate. The structure was confirmed by IR and NMR analysis.
Reaction SMILES: [OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[CH:13])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15].Br[C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[F:38].C(OCC)(=O)C.O>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][CH:2]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])[CH2:7][C@@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Fc1cccc(F)c1Br
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2c(F)cccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 40.1 %

Procedure:
A mixture of 1.07 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine-3-carboxylate in 10 cm3 of triethylamine was stirred for 5 minutes under an inert atmosphere at a temperature in the region of 20° C. 0.156 g of tetrakis(triphenylphosphine)palladium, 0.051 gof cuprous iodide, and 0.78 g of 1-bromo-2,6-difluorobenzene were added. The mixture was stirred for 3 hours 30 minutes at a temperature in the region of 80° C. After cooling to approximately 20° C., the reaction mixture had 30 cm3 of ethyl acetate and 30 cm3 of water added. After stirring for 10 minutes, the mixture was separated by settling. After separating off the organic phase, the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 50 g), elution was carried out with pure ethyl acetate, and first a fraction of 300 cm3 were collected, followed by 38-cm3 fractions. Fractions 6 to 16 were combined and concentrated as above. 0.55 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with a pale yellow color.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:11])(=[O:14])[CH3:13]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C(=O)Cc2cc(F)ccc21
Temperature: 25 °C

Procedure:
At 170° C. 3.0 g (20 mmol) 5-fluoroindolinone were stirred for 3 h in 10 mL (98 mmol) acetic anhydride. After cooling to RT the mixture was poured onto 200 mL ice water, the precipitated substance was suction filtered and washed with 100 mL water. The solid was recrystallised from 100 mL water and 50 mL ethanol at boiling temperature. The precipitated product was suction filtered, washed with 30 mL water and dried in the CAD.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C@:9]3([CH3:14])[C:11]([CH3:12])([CH3:13])[C@@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[N:3]1[CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[C:17]([F:16])([F:26])[F:27]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@@]1(C)CC[C@@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(F)(F)F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 16 %

Procedure:
A solution of (4R,7S)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 48; 115 mg, 0.55 mmol) and 2-(trifluoromethyl)benzyl bromide (133 mg, 0.55 mmol) in dimethylformamide (5.6 mL) was heated at 100° C. overnight. The solvent was evaporated and the residue was purified on a Biotage chromatography system, eluting with 0-5% methanol/dichloromethane. The resulting clear oil was taken up in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and water, dried (sodium sulfate), filtered, evaporated, and triturated with ether to give (4R,7S)-1,7,8,8-tetramethyl-2-(2-trifluoromethyl-benzyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (32 mg, 16%) as a white solid. APCI(+)-MS (M+H) 365.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:10]([C:23](=[O:46])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:25])[C:9]1=[O:47])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:23](=[O:46])[C@@H:24]([NH:26][C@H:27]([C:36]([OH:38])=[O:37])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH3:25])[C:9]1=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCCCCCCC[C@H](N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O)C(=O)O
Yield: 90.9 %

Procedure:
4.3 g of benzyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 200 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 2.81 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-n-nonyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid are obtained as colorless crystals. Yield: 90.9%
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:14][CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.C(OC(=O)C)(=O)C.[N+:28]([O-])([OH:30])=[O:29]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:11]2[C:15]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[C:14]([N+:28]([O-:30])=[O:29])[CH:13]=[N:12]2)=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)Nc1ccnn1-c1nn2c(c1Cl)CCCC2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
8.72 g (29.7 mmol) N-[1-(3-Chloro-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)-5-pyrazolyl]propionamide was suspended in 33 ml acetic acid. Under ice cooling, at 0°-5° C., 3.31 g (32.5 mmol) acetic anhydride was added. 1.93 g (31 mmol) Fuming nitric acid was added dropwise. After stirring for 6 hours at room temperature, the mixture was concentrated. The residue was taken up in dichloromethane, neutralised with aqueous sodium hydrogen carbonate and washed with aqueous sodium chloride. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane/ethyl acetate 1:1).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Cu][C:25]#[N:26]>CN1CCCC1=O>[O:15]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[N:5]1[CH2:4][C:3]1[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=1[C:25]#[N:26]
Reactant: COc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: COc1cc(C#N)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of 2-(2-bromo-4,5-dimethoxy-benzyl)isoindole-1,3-dione (26.63 g, 0.07079 mol) and copper (I) cyanide (12.7 g, 0.1416 mol) in N-methyl-2-pyrrolidinone (266 mL) was heated to reflux for 18 h under nitrogen. The resulting mixture was concentrated in vacuo and the resulting residue stirred with a mixture of chloroform (250 mL) and water (250 mL) for 30 min. The resulting suspension was filtered through CELITE and the layers separated. The organic layer was extracted with brine (2×), dried over MgSO4, filtered and concentrated in vacuo. The resulting solid was crystallized from methylene chloride/methanol (500 mL) to yield 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5-dimethoxy-benzonitrile as a white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9][OH:10])[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1.[H-].[Na+].[CH3:27]I>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([CH2:9][O:10][CH3:27])[N:6]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:12])[CH2:5]1
Reactant: CON=C1C[C@@H](CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@@H]1CC(=NOC)CN1C(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of alcohol (2) (EZ mixture, 20 mg, 0.06 mmol) and sodium hydride (3 mg, 0.12 mmol) in tetrahydrofuran (1 ml) under argon, was added methyl iodide (7.7 μl, 0.12 mmol). The reaction mixture was stirred overnight and quenched with water. The mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4) and concentrated in vacuo. The crude was purified on silica gel preparative chromatography using DCM: MeOH 100:0 then 95:5.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:12][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Yield: 73.5 %

Procedure:
Methyl 4-[3-(1-quinolin-6-ylcyclopropyl) [1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (300 mg, 0.7 mmol) was dissolved in 6 ml of THF-MeOH—H2O (3:1:1). To the solution was added a solution of 2.0 M of lithium hydroxide in water (710 μL) with stirring under N2 atmosphere. The mixture was stirred at RT for 1 h, and then neutralized with aqueous HCl solution (1.0 M, 1.420 mL). The white precipitate formed was collected by filtration, and dried in-vacuo to give the desired product (210 mg, 72%). Analytical LCMS: m/z 409.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:6])[OH:9]
Reactant: CCOP(=O)(CCCN)c1ccccc1
Agent: Cl
Product: NCCCP(=O)(O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of 6.83 g of ethyl 3-aminopropyl(phenyl)phosphinate and 30 ml of 20% hydrochloric acid is refluxed with stirring for 4 hours. The clear solution is evaporated to dryness and the residue is recrystallized from methanol/propylenoxide to give 3-aminopropyl(phenyl)phosphinic acid as a white solid, m.p. 298°-300°.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[N:8]=[CH:7][N:6]=1.[O:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:32]([CH:28]3[CH2:29][CH2:30][CH2:31][O:27]3)=[O:33])[CH2:15][CH2:14]2)[C:10]=1[CH3:11]
Reactant: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCNCC1
Reactant: O=C(O)C1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)C2CCCO2)CC1
Temperature: 120 °C
Yield: 81.3 %

Procedure:
Mixture of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(piperidin-4-yloxy)-pyrimidine (76 mg, 0.2 mmole), tetrahydro-furan-2-carboxylic acid (0.26 mmole, 1.3 eq), HATU (0.26 mmole, 1.3 eq), and TEA (0.4 mmole, 2 eq) in 2 mL THF was heated under microwave irradiation at 120° C. for 30 minutes. Mixture was purified by HPLC to give compound C164 as a yellow solid (78 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.85-2.17 (m, 8H), 2.21 (s, 3H), 3.10 (s, 3H), 3.75-3.80 (m, 2H), 3.86-3.91 (m, 2H), 3.96-4.01 (m, 2H), 4.68 (t, 1H), 5.40-5.45 (m, 1H), 7.44 (t, 1H), 7.78-7.82 (m, 2H), 8.21 (s, 1H). Exact mass calculated for C22H26FN3O6S 479.2, found 480.3 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH2:10][C@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of tert-butyl N-(4-[[(12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2 (7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (200 mg, 0.36 mmol, 1.00 equiv) in 6 mL of THF was added TBAF (186 mg, 0.71 mmol, 2.00 equiv) at room temperature and the resulting solution was stirred overnight at ambient temperature. The reaction was then quenched with water, extracted with 3×30 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Purification by column chromatography on silica gel with ethyl acetate/petroleum ether (1:2) afford 129 mg (81%) of the desired tert-butyl N-(4-[[(12R)-12-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH2:16])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].Cl.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:20]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=3[S:22][CH:23]=2)[C:8]2[C:13]([C:14]=1[CH2:15][NH:16][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CCOC(=O)c1c(CNS(C)(=O)=O)c2cc(F)ccc2n1Cc1csc2ccc(F)cc12

Procedure:
3-Aminomethyl-5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester; salt with hydrogen chloride was reacted with methanesulfonyl chloride as described in Example 77.1. to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give 5-fluoro-1-(5-fluoro-benzo[b]thiophen-3-ylmethyl)-3-(methanesulfonylamino-methyl)-1H-indole-2-carboxylic acid as a colorless solid. MS: 449.3 ([M−H]−).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]2[C:21]([C:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1.[H][H]>O1CCCC1.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[C:11]1[CH:29]=[CH:28][C:14]([O:15][C:16]2[C:21]([CH:22]3[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23]3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: OC1C=C(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2Oc2ccc(C(O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A solution of 3-(2-(4-((1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)phenoxy)pyridin-3-yl)cyclopent-2-enol (780 mg, 1.953 mmol) in Tetrahydrofuran (50 mL) was treated with palladium, 10% wt. on activated carbon (208 mg, 0.195 mmol) under nitrogen. The reaction flask was equipped with a hydrogen balloon and cycled through vacuum-hydrogen cycles (3×). The reaction was heated to 40° C. under hydrogen. After 5 h, the reaction was cooled to 23° C., and filtered through celite. The filter cake was washed with tetrahydrofuran (200 mL), the filtrates combined and concentrated, affording the product as a white solid. MS (ESI, pos. ion) m/z: 402.1 (M+1).
Reaction SMILES: [NH2:1][NH2:2].[CH2:3]([O:10][C@@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:12]=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[NH:1]([C:12]([C@H:11]([C@@H:14]([C@@H:23]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[OH:24])[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:13])[NH2:2]
Reactant: NN
Reactant: O=C[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: NNC(=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1

Procedure:
To a solution of 3.8 g (119 mmoles) of anhydrous hydrazine in 10 ml of absolute methanol a solution of 5 g (11.9 mmoles) of 2,3,5-tri-O-benzyl-D-arabinose in 10 ml of absolute tetrahydrofuran (THF) is added dropwise while stirring and cooling in an ice bath at a moderate speed. After 10 minutes the ice bath is removed and the solution is stirred for 6 hours at room temperature. Then the solvent is removed with the superfluous hydrazine, and the remaining yellowish oil is dried for removal of the last traces of hydrazine for one day under a continuous oil pump vacuum.