Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=O)=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:20][NH2:21]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6]([C:12]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[N:20][NH:21][C:8]2=[O:9])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(C(=O)c2cccs2)c(C(=O)O)c1
Solvent: O
Product: COc1ccc2c(-c3cccs3)n[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-(thiophene-2-carbonyl)benzoic acid with hydrazine hydrate.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6](=O)[CH2:7][CH2:8][O:9][CH3:10].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[S:19])=[CH:16][CH:15]=1.CO>ClCCl>[CH3:2][O:3][C:4]([C:5]1[S:19][C:18]([C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:20][C:6]=1[CH2:7][CH2:8][O:9][CH3:10])=[O:12]
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: COCCC(=O)CC(=O)OC
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: COCCc1nc(-c2ccc(Cl)cc2)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
Add a 1.0 M solution of sufuryl chloride in dichloromethane (20.0 mL, 20.0 mmol) dropwise to a solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (3.0 g, 18.8 mmol) in dichloromethane (20.0 mL) at 0° C. and stir under nitrogen at 0° C. for 2 h. Concentrate the reaction mixture on a rotavap (rotary evaporator), keeping the bath temperature at RT. Add 4-chlorothiobenz-amide (3.67 g, 21.5 mmol) to the residue, followed by methanol (30.0 mL) and heat to 60° C. for 18 h. Quench the reaction with water and extract with EtOAc (2×). Combine the organic portions, wash with brine, dry over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on silica gel, using a gradient of EtOAc/Hexane (0-60%) to give the title compound (3.3 g, 57%). Exact mass=311.0, MS (ES+) 312.0 (M+1). 1H NMR (CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.88 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.8 Hz), 3.38 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=3)=[N:14]2)=[O:9])[CH:4]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.CCOC(C)=O>[N:29]1([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[C:22]([F:24])[C:21]([C:25]#[N:26])=[C:20]([Cl:27])[CH:19]=4)=[N:14]3)=[O:9])[CH:4]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(Cn2ccnc2)on1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
(S)-5-(Bromomethyl)-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)isoxazole-3-carboxamide (0.137 mmol, 0.064 g) was suspended in DMF (5 ml). Imidazole (2.74 mmol, 0.187 g) was added and the resulting mixture was stirred at RT for 2.5 h. The reaction mixture was heated to 60° C. for 1.5 h. The mixture was diluted with EtOAc and washed four times with water. The organic phase was dried, filtered and evaporated. The crude product was purified by preparative HPLC. 0.017 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 4.31 (d, 2H), 4.37-4.50 (m, 1H), 5.50 (s, 2H), 6.63 (s, 1H), 6.94 (s, 1H), 6.99 (d, 1H), 7.22-7.24 (m, 1H), 7.76 (s, 1H), 7.83 (d, 1H), 7.84-7.88 (m, 1H), 7.96 (s, 1H), 8.81 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[C:43]([CH3:45])[N:42]=[C:41]([CH3:46])[CH:40]=2)[CH:34]=1)=[O:32])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][CH3:17])[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[C:41]([CH3:46])[N:42]=[C:43]([CH3:45])[CH:44]=2)[CH:34]=1)=[O:32])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CCCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)nc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J35) (251 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow solid (172 mg, 49%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:19])[N:11]=[C:12]3[CH:17]=[C:16](C)[CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1.[Br:32]Br.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:32][CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]1=[O:19]
Reactant: Cc1ccc2c(-c3ccccc3)ccc(=O)nc2c1
Reactant: BrBr
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccccc2)CC1Br
Temperature: -70 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
To a 200 mL three neck round-bottomed flask equipped with a nitrogen inlet and septum were added 5.48 grams (21.8 mmol) 5-phenyl-8-methyl-2-oxobenzazepine, 100 mL dichloromethane, and 4.55 grams (21.8 mmol) phosphorus pentachloride. After dissolution, 1.85 mL (22.9 mmol) pyridine was added, and the solution cooled to -70° C. To the stirring solution (some precipitate appeared at this temperature, but did not affect the reaction) was added a solution of 1.12 mL (21.8 mmol) bromine in 10 mL methylene chloride dropwise over 20 minutes. The reaction was then allowed to warm quickly (10 minutes) to 0° C., and 50 mL of saturated aqueous sodium bisulfite solution was added. The reaction was then diluted with methylene chloride and allowed to stand under sodium bisulfite solution with periodic shaking for 2 hours, until the organic phase no longer exhibited a reddish color. The organic phase was then dried over sodium sulfate and evaporated. The residue was suspended in methylene chloride and filtered, and the solid dissolved to afford 3.39 grams (47%) of product as a white solid. The filtrate was adsorbed onto silica gel and chromatographed using 7:3 hexane/ethyl acetate as eluant to afford additional product as a white solid, 1.38 g, total 5.14 (71%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16]C(C)(C)[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:41])[CH:23]2[CH2:26][CH:25]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)=[O:29])[CH2:24]2)[O:12]1>C(O)(C(F)(F)F)=O.O>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:12][C@H:13]([CH2:21][N:22]([CH3:41])[CH:23]2[CH2:26][CH:25]([NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:33][CH:32]=3)=[O:29])[CH2:24]2)[C@@H:14]([OH:18])[C@H:15]1[OH:16]
Reactant: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(NC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(NC(=O)Nc2ccc(C(C)(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
A solution of 1-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)-3-(4-(tert-butyl)phenyl)urea (125 mg, 0.23 mmol) in TFA (0.90 mL) and 0.10 mL of water were stirred for 1 hour at room temperature. The reaction was concentrated to dryness, dissolved in MeOH (5 mL) and K2CO3 (60 mg) in 0.5 mL of water was added dropwise. The reaction was stirred at rt for 0.5 h and concentrated to obtain the residue which was purified by prep-TLC (DCM:MeOH:NH4OH=300:30:8, V/V) to obtain the desired compound (75 mg, Yield: 65%) as pale white solid. 1H NMR (500 MHz, MeOD): δH 8.27 (s, 1H), 8.21 (s, 1H), 7.28-7.20 (m, 4H), 6.00-5.99 (m, 1H), 4.77-4.75 (m, 1H), 4.28-4.23 (m, 2H), 3.92-3.88 (m, 1H), 2.92 (brs, 1H), 2.83-2.81 (m, 2H), 2.59-2.56 (m, 2H), 2.32 (s, 3H), 1.74-1.64 (m, 2H), 1.27 (s, 9H) ppm; ESI-MS (m/z): 525.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3OCCO3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:21]O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(C3OCCO3)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 75 %

Procedure:
2.6 g of 2-[p-(4-methoxy phenyl)-phenyl]-1,3-dioxolane, 0.917 g of hydroxylamine hydrochloride, 40 ml of 1.8 M hydrochloric ethanol and 10 ml of ethanol are introduced into a 100 ml three-necked flask under nitrogen. The reaction mixture is heated to reflux for 4 hours then concentrated under vacuum. The residue is taken up in 30 ml of water, then 220 ml of methyl ter-butyl ether (MTBE) is added. The organic phase is separated and the aqueous phase is extracted with MTBE (2×20 ml). The organic phases are combined, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulphate and concentrated under vacuum (yield: 75%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]Br)=[CH:5][CH:4]=1.[CH3:11][C:12]1([CH3:21])[CH2:17][CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[NH:13]1>COCCOCCOC>[C:6]1([CH2:9][N:13]2[C:14]([CH3:19])([CH3:20])[CH2:15][CH:16]([OH:18])[CH2:17][C:12]2([CH3:21])[CH3:11])[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[C:14]([CH3:20])([CH3:19])[CH2:15][CH:16]([OH:18])[CH2:17][C:12]2([CH3:21])[CH3:11])=[CH:4][CH:5]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: BrCc1ccc(CBr)cc1
Solvent: COCCOCCOC
Product: CC1(C)CC(O)CC(C)(C)N1Cc1ccc(CN2C(C)(C)CC(O)CC2(C)C)cc1

Procedure:
In a 500 -milliliter, round-bottomed flask are placed 11.4 grams of α, α'-dibromo-p-xylene, 25.2 grams of 2, 2, 6, 6-tetramethyl-4-hydroxypiperidine and 120 milliliters of diglyme (dimethyl ether of diethylene glycol). The contents are refluxed for 19 hours with vigorous stirring and filtered hot. The diglyme from the filtrate is removed by distillation. The remaining solid is washed with methanol. The solid is then washed repeatedly with ether. The 1, 1'-(p-phenylenedimethylene) bis(2, 2, 6, 6-tetramethyl-4-piperidinol) is obtained as a white crystalline solid, is dried in a vacuum oven and has a melting point of 237°-239°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:17])=O>[OH-].[Na+]>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(N)nc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1c(N)nc2ccccc2c1Cl
Temperature: 110 °C

Procedure:
The mixture of 10 g of 2-amino-3-cyano-4-hydroxyquinoline and 15 ml of phosphoryl chloride is heated under stirring at 110° C. The reaction mixture is cooled down, poured onto 100 ml of ice-water and neutralized with 60 ml of 10% sodium hydroxide solution. The resulting yellow precipitate is filtered off, washed with 50 ml of water. After drying 7.5 g of the title compound is obtained, mp.: 210° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1ccc(F)cc1
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(F)cc2)n1C

Procedure:
The title compound, MS: m/e=286.8 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-ethynyl-4-fluorobenzene.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[S:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH2:24][CH2:25][C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CCC1=CCCCC1)Oc1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
0.18 g (0.04 equivalent) of Pd(PPh3)4 and then 1.2 g (0.0084 mol) of 5-chloro-2-thiopheneboronic acid are added to a solution of 1.4 g (0.0038 mol) of ethyl 2-[(4-bromophenyl)oxy]-4-cyclohex-1-en-1-ylbutanoate in 20 ml of dimethoxyethane. 4.2 ml of 2M sodium carbonate solution are added at room temperature. The reaction mixture is stirred overnight and then refluxed for 2 hours. After cooling to room temperature, the mixture is taken up in water and extracted with ethyl acetate. The extract is washed with 1N sodium hydroxide and then with saturated aqueous NaCl solution and finally dried over Na2SO4. After concentrating, the black oil obtained is purified by flash chromatography (95/5 heptane/ethyl acetate). 1.1 g of a thick oil are obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][C:26](=O)[CH2:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32]>C(O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:26]([CH3:25])[C:27]=2[C:28](=[O:33])[CH2:29][CH2:30][CH2:31][CH3:32])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCCCC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Solvent: CCO
Product: CCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
A mixture of 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride (25.0 g), 2,4-octanedione (10.5 g) and ethanol (500 ml) was stirred under reflux for 2 hours. The solvent was evaporated under reduced pressure. The residue was poured into saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. The chloroform was evaporated, and the residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform-ethanol (20:1, v/v) gave 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-methyl-3-valerylquinoline- This compound was recrystallized from ethanol to give colorless prisms. mp. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=O)[O:24]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.[H-].[NH2:33][NH2:34].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([NH:33][NH2:34])=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3F)CC2)cc1
Reactant: NN
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3F)CC2)cc1
Yield: 79.5 %

Procedure:
To a solution containing 5 (0.3 g, 0.7 mmol) and hydrazine monohydride (0.19 mL, 3.7 mmol) in 1,4-dioxane. The reaction mixture was stirred and heated to reflux for 4 h. After cooling to room temperature water was added and the mixture was stirred for 30 min. The precipitated solid was filtered and the solid was washed with acetonitrile and then dried under vacuum to obtain the hydrazinecarboxamide intermediate 6 (0.2 g, 82%).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1.O[CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[N:7]=[CH:6][N:5]2[CH:16]1[CH2:17][CH2:12][CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Nc1ncnc2[nH]cnc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(n2cnc3c(N)ncnc32)C1
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To a solution of 9H-purin-6-amine (945 mg, 7 mmol, 1.0 eq) in THF (1 mL) was added tert-butyl 3-hydroxypiperidine-1-carboxylate (2.996 g, 14 mmol, 2.0 eq) and PPh3 (3.67 g, 14 mmol, 2.0 eq). After stirring for the solution for 15 min, DIAD (2.83 g, 14 mmol, 2.0 eq) was added the reaction was continued to be stirred rt for 1 h. The solvent was removed in vacuo and the residue was purified on a silica gel column (PE/EA=5:1) to afford the title compound as a yellow solid (245 mg, yield 11%). 1H NMR (400 MHz, CD3OD) δ: 8.44 (s, 1H), 8.42 (s, 1H), 5.04-4.98 (m, 1H), 3.77-3.73 (m, 1H), 3.68-3.62 (m, 1H), 3.52-3.48 (m, 1H), 3.18-3.11 (m, 1H), 2.45-2.32 (m, 2H), 2.22-2.17 (m, 1H), 2.05-1.97 (m, 1H), 1.49 (s, 9H). ESI-MS: 319.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[NH:13]2)[C:2]1C=CC=CC=1.C(OCC)(=[O:24])C>[Pd]>[C:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[NH:13]2)(=[O:24])[CH3:2]
Reactant: COC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: COC(=O)c1cc2c(OC(C)=O)cccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 4-benzyloxyindole-2-carboxylate (48 g) in ethyl acetate (1 litre) at 50-60° C. was hydrogenated over 5%Pd-C catalyst (4.0 g) at 1 atmosphere pressure for 6 hours, until 3.7 litres of hydrogen was absorbed. The catalyst was filtered off and washed with warm ethyl acetate(100 ml). To the combined filtrates was added acetic anhydride (40 ml) and 4-dimethylaminopyridine (1.0 g), and the solution was stirred for 1 hour at 25° C. Ethanol (15 ml) was added and the solution reduced to halt volume by evaporation in vacuo, then hexane (1 litre) was added to cause crystallisation of the product as white needles (37 g, 93%). NMR d (CD3SOCD3) 2.34 (s, 3H), 3.85 (s, 3H), 6.80 (d, 1H), 7.06 (s, 1H), 7.23 (t, 1H), 7.29-7.35 (m, 1H), 12.1 (bs, 1H); M/z (−) 232 (M-H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[Si:25]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
Benzyl 3-hydroxypropylcarbamate (15 g, 72 mmol) was treated with imidazole (10 g, 146.9 mmol) and TBSCl (12 g, 79.6 mmol) in DMF (10 ml) at 0° C. After warming up the reaction mixture to room temperature, it was stirred for 30 minutes. The resulting solution was quenched with water (50 ml), and then extracted with diethyl ether (50 ml×2) twice. After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAc:Hx=1:10) to afford title compound (23 g, 98%) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[CH3:15][O:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:23][O:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][O:16][CH3:15])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: COCOCCCON
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOCCOC
Product: COCOCCCONc1nc(NC=O)nc(Cl)c1NC=O
Temperature: 100 °C

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.75 g, 7.4 mmol), 3-(methoxymethoxy)propoxyamine (1.0 g, 7.4 mmol) and N,N-diisopropylethylamine (2 g, 15.5 mmol) in dry diglyme was heated to 100° C. for 2 hr. The cooled reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate:hexane (50:50) then ethyl acetate to give the title compound as a yellow oil which was crystallised from ethyl acetate (1.2 g, 50%) mp 136°-8° C. νmax (KBr) 3240, 2920, 2880, 1705, 1640, 1590, 1565, 1495, 14650, 1410, and 1380 cm-1 ; δH [(CD3)2SO]1.85 (2H, quintet, J=6.3 Hz, CH2CH2CH2), 3.24 (3H, s, OCH3), 3.58 (2H, t, J=6.3 Hz, CH2OCH2OCH3 ), 3.94 (2H, t, J=6.3 Hz, CH2ONH), 4.5 (2H, s, OCH2O), 8.15 (1H, s, NHCHO), 9.26 (1H, d, J=9.6 Hz, collapses to singlet on D2O, NHCHO), 9.4 (1H, s, D2O exchangeable NHOCH2), 10.73 (1H, s, D2O, exchangeable NHCHO), 10.84 (1H, d, J=9.6 Hz, D2O exchangeable, NHCHO).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([N:17](C)[C:18](=O)C(F)(F)F)[CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)=[O:4].O.S(=O)(=O)(O)O.[OH-].[Na+]>CC(=O)OCC>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11]([F:16])([F:12])([F:13])([F:14])[F:15])[CH:8]=[C:7]([NH:17][CH3:18])[CH:6]=1)=[O:4]
Reactant: CN(C(=O)C(F)(F)F)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
N-[3-(2-Bromoacetyl)-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (O1.075; 1.2 g) was admixed with water (15 ml), and concentrated sulfuric acid (15 ml) was added dropwise while stirring and cooling with ice. The mixture was heated to 80° C. and stirred at this temperature for 7 h. After cooling, the reaction mixture was slowly added to a mixture of 10N sodium hydroxide solution and EA, and the aqueous phase was extracted five times with EA. The combined organic phases were dried over magnesium sulfate and, after filtering off the desiccant under reduced pressure, dried. The residue was purified by means of preparative HPLC. The product fractions, each of them clean, were combined, freed of the acetonitrile under reduced pressure, neutralized with sodium hydrogencarbonate and extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after filtering off the desiccant, dried under reduced pressure. 420 mg of the title compound were isolated. LC-MS Rt: 1.64 min [M+H]+:354.0
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5]C[CH2:3][CH2:2]1.Cl.Cl.Cl.NC1CCN(CCN2CCC([OH:50])CC2)CC1>>[OH:50][CH:5]1[CH2:3][CH2:2][N:1]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Product: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see Example 2) and amine 21.