Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=[O:5])CCC.[Na+].C([O-])(=O)[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+].S(=O)(=O)(O)O>>[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH3:9]
Reactant: O=C([O-])C=Cc1ccccc1
Reactant: CCCC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
The same medium and parameters as the inoculum were used. A 500 ml flask containing 100 ml broth was sterilized for 20 min. at 121° C. A 2.5 ml aliquot of sterilized 20% sodium butyrate solution (pH 7.0) and 1 ml. of the 24 hours grown culture were added. The flask was incubated at 30° C. and 150 rpm for 24 hours. Sterile 10% sodium cinnamate (pH 7.0) was added to each flask as follows: 5 g/l at 24 hours, 4 g/l at 72 hours, and 6 g/l at 80 hours. Periodically, 2 ml. samples of broth were acidified to pH 4.0 using 50% sulfuric acid, extracted with an equal volume of ethyl acetate, and analyzed by GC. The acetophenone concentration was estimated by external standard. At the conclusion of the fermentation, the culture broth was acidified to pH 4 as above and extracted twice with ½ volume of ethyl acetate each time. The extracts were combined and solvent was removed under vacuum using a rotary evaporator. The crude product was distilled in a micro-distillation oven and the distillate analyzed by GC. The yield of 1.8 g/L having a purity of 94.3% was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cnc2ccccc2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available quinoline-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.60 min.; [M+H]+: 365.01 g/mol.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.OO.O.C(=O)(O)[O-].[Na+].[ClH:21]>>[Cl:21][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(F)(F)F)c(N)n1
Reactant: Cl
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)c(C(F)(F)F)cc1Cl
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
6-Methyl-3-(trifluoromethyl)pyridin-2-amine (59 mg, 335 μmol, Eq: 1.00) was suspended in 37% HCl aq (4.13 ml) and 35% hydrogen peroxide aq (488 mg, 440 μl, 5.02 mmol, Eq: 15) was added dropwise. The mixture was stirred for 20 min. Water (50 ml) was added. The mixture was alkalized by addition of sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (70 mg, 99.2%) was obtained as a light yellow solid by column chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=211.2 (M+H+)
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C@H:19]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:17])=[CH:11][CH:10]=1)[CH2:6][CH2:7][Cl:8]>CCOCC.C(OCC)(=O)C>[ClH:2].[Cl:2][CH2:3][CH2:4][N:5]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C@H:19]([C:29]([OH:31])=[O:30])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:17])=[CH:13][CH:14]=1)[CH2:6][CH2:7][Cl:8]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Yield: 186.3 %

Procedure:
A saturated solution of hydrogen chloride in ether (120 ml) was added to a solution of ditertbutyl N-(-4-[N,N-bis-(2-chloroethyl)amino]-phenylcarbamoyl)-L-glutamate (4.4 g) in ethyl acetate (20 ml). After 1 hour at ambient temperature the mixture was evaporated to a solid. This solid was triturated with ether to obtain N-(4-[N,N-bis(2-chloroethyl)amino]phenylcarbamoyl)-L-glutamic acid hydrochloride (3.5 g) as a grey solid m.p=148°-150° C. (see Scheme 3)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:11][CH:12]=[O:13])=[C:4]([F:14])[CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]1[CH:29]=[CH:28][C:22]2[N:23]=[C:24]([S:26][CH3:27])[S:25][C:21]=2[CH:20]=1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N:11]([CH2:18][C:19]2[CH:29]=[CH:28][C:22]3[N:23]=[C:24]([S:26][CH3:27])[S:25][C:21]=3[CH:20]=2)[CH:12]=[O:13])=[C:4]([F:14])[CH:3]=1
Reactant: O=CNc1c(F)cc(Br)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(CN(C=O)c3c(F)cc(Br)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
To a stirred solution of N-(4-bromo-2-fluoro-6-nitrophenyl)formamide (2.79 g, 10.61 mmol) from the previous step in anhydrous DMF (40 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 485 mg, 12.13 mmol). The mixture was stirred at 0° C. for 15 min, then allowed to warm to rt. To the reaction mixture was added a solution of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (3.04 g, 13.24 mmol) from Step 3 of Example 3 in DMF (10 mL), and the mixture was stirred at rt for 15 h. The mixture was partitioned between water and DCM and the organic layer was separated and washed sequentially with water and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford N-(4-bromo-2-fluoro-6-nitrophenyl)-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)formamide (4.8 g, 98%) as an oil, which was not purified further. LCMS (ESI) m/z 456 and 458 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:13][N:14]([CH3:19])[S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][N:14]([CH3:19])[S:15]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)(=[O:17])=[O:16]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1cn[nH]c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cccn1
Temperature: 25 °C
Yield: 106.6 %

Procedure:
To a solution of pyrazole (10.0 g, 147 mmol) in dichloromethane (150 mL), triethylamine (26.6 mL, 192 mmol) and N,N-dimethylsulfamoyl chloride (20.0 mL, 181 mmol) were added and the reaction mixture was heated to reflux for approximately 60 h. The reaction mixture was then cooled to ambient temperature and filtered through a pad of silica gel using dichloromethane as an eluent. The filtrate was then concentrated under reduced pressure and treated with diethyl ether (100 mL) resulting in the formation of a solid. The suspension was filtered, and the precipitate was washed with diethyl ether. The combined filtrates were combined and concentrated in vacuo to give 27.46 g of the title compound. This compound was of sufficient purity to use in subsequent reactions. 1H NMR (CDCl3) δ 2.94 (s, 6H), 6.40 (s, 1H), 7.75 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[N-:17]=[N+:18]=[N-:19].[Na+]>CS(C)=O.O>[N:17]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CBr)c2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of methyl 4-(bromomethyl)-1-naphthoate (30 g, 0.107 mol) in anhydrous DMSO (300 mL) was added NaN3 portion wise (14 g, 0.215 mol) at 0° C. and stirred at rt for 16 h. Then the reaction mixture was diluted with water (500 mL), extracted with EtOAc (2×250 mL), washed with water, brine and dried over MgSO4. The solvent was removed under vacuum to give methyl 4-(azidomethyl)-1-naphthoate (20 g, 77%).
Reaction SMILES: C(N(CC)CC)C.[S:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]1.Cl.[CH3:17][NH:18][O:19][CH3:20].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:13]([C:12]1[S:8][CH:9]=[N:10][CH:11]=1)=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1cncs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cncs1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (2.77 mL, 19.9 mmol) was added slowly to a mixture of commercially available thiazole-5-carboxylic acid (1.03 g, 7.98 mmol), N,O-dimethylhydroxylamine hydrochloride (0.778 g, 7.98 mmol), and EDCI (1.83 g, 9.57 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 72 hours then quenched with saturated aqueous NaHCO3. Water (50 mL) was added followed by additional CH2Cl2. The mixture was stirred for 10 minutes and layers were separated. The CH2Cl2 layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure and the residual oil was chromatographed (CH2Cl2/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: [C:1]([O:11]C)(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH:25][C:1](=[O:11])[CH:2]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:3])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COC(=O)C(O)c1ccccc1
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)C(O)c2ccccc2)cc1OC
Reaction time: 5 h

Procedure:
33.2 g (0.2 Mol) of methyl mandelate and 72 g (0.4 Mol) of 2-(3,4-dimethoxyphenyl)-ethylamine are heated to 160°-165° C. under an N2 atmosphere with stirring, for 5 hours using a descending condenser (to remove the methanol released). The cooled residue-is dissolved in 300 ml of ethyl acetate, washed twice with 100 ml of 2N HCl, once with saturated NaHCO3 solution and saturated NaCl solution, dried over MgSO4 and distilled off from the solvent.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:16][C:17]([C:19]2[C:28]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:14][C:13]2[CH:12]=[N:11][C:10]([CH3:15])=[CH:9][C:8]=2[CH2:7]1)=[O:5])C.[OH-].[K+]>CCO.O>[CH3:15][C:10]1[N:11]=[CH:12][C:13]2[CH2:14][C:6]([NH:16][C:17]([C:19]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=[CH:21][CH:20]=3)=[O:18])([C:4]([OH:5])=[O:3])[CH2:7][C:8]=2[CH:9]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2cnc(C)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc2c(cn1)CC(NC(=O)c1cccc3c1CCCC3)(C(=O)O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
The mixture of 3-methyl-6-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester (82) and KOH (1 g, 17.9 mmol) in EtOH (5 mL) and water (0.3 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl dropwise until no more precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (83) as colorless oil (20 mg, 22%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([N:6]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][C:7]2=[O:14])=[CH:2]1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7](=[O:14])[CH:8]=1
Reactant: O=Cc1ccn(-c2ccsc2)c(=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1cc(CO)ccn1-c1ccsc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of 1-thiophen-3-yl-2-oxo-1,2-dihydro-pyridine-4-carbaldehyde (0.27 g, 1.3 mmol) in methanol (20 mL) is cooled to 0° C. in an ice-water bath and then treated with sodium borohydride (50 mg, 1.3 mmol). After stirring at 0° C. for two hours, the reaction mixture is quenched by the addition of 10% aqueous hydrochloric acid. The mixture is extracted with ethyl acetate. The combined organic extracts were washed once with saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure to provide 4-hydroxymethyl-1-thiophen-3-yl-1H-pyridin-2-one (0.18 g, 67%), which is used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18](F)=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:32]#[N:33].[CH3:34][O:35][CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:38][CH2:37][CH2:36][O:35][CH3:34])=[C:19]([O:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:32]#[N:33]
Reactant: COCCO
Reactant: COc1cc(Nc2c(C#N)cnc3cc(F)c(OCCN4CCOCC4)cc23)c(Cl)cc1Cl
Product: COCCOc1cc2ncc(C#N)c(Nc3cc(OC)c(Cl)cc3Cl)c2cc1OCCN1CCOCC1

Procedure:
Following the procedure used to prepare Example 15, 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-6-(2-morpholin-4-ylethoxy)-3-quinolinecarbonitrile (102 mg, 0.21 mmol) and 2-methoxyethanol provides 86 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(2-methoxyethoxy)-6-(2-morpholin-4-ylethoxy)3-quinolinecarbonitrile, mp 158-159° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[I:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([I:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(I)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-iodobenzoyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 574/576 (M-+H). 1H-NMR (DMSO-d6) δ 3.20-3.50 (m, 4H), 3.62-3.71 (m, 2H), 4.25 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.10 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.22 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.2 Hz, 1H), 7.02 (d, J=8.2 Hz, 2H), 7.04 (t, J=8.2 Hz, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.60 (d, J=8.2 Hz, 1H), 7:61 (d, J=8.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].CC1(C)[O:34][C@H:33]([CH2:35][O:36][NH2:37])[CH2:32][O:31]1>>[OH:34][C@@H:33]([CH2:32][OH:31])[CH2:35][O:36][NH:37][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: CC1(C)OC[C@@H](CON)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CO)c(=O)n(C)c1=O

Procedure:
Example 37 was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with (S)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (See, Bailey et al., J. Med. Chem., 34, 1991, 51-65), followed by acid hydrolysis of the resulting material. 1H NMR (400 MHz, CDCl3) δ 7.46 (m, 2 H) 6.79 (t, J=8.0 Hz, 1 H) 3.89 (m, 3 H) 3.66 (m, 1 H) 3.55 (m, 1 H) 3.31 (s, 3 H) 3.02 (s, 3 H). [M+H] calc'd for C16H18FIN4O6, 509; found, 509.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[F:12])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[F:12][C:6]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1cccc(F)c1F
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(F)c1F
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A solution of 2-bromo-1-(2,3-difluorophenyl)ethanone (7.20 g, 30.6 mmol) and potassium thiocyanate (3.01 g, 30.6 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (85 ml) was poured to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 5.67 g (86.8%) of the desired product as an oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1.CCCC[N+](CCCC)(CCCC)CCCC.[FH:39].F.[F-]>>[F:39][CH2:3][CH:2]([OH:1])[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1
Reactant: F
Reactant: O=C(OCc1ccccc1)N1CCC(OCC2CO2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(OCc1ccccc1)N1CCC(OCC(O)CF)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of benzyl 4-(oxiran-2-ylmethoxy)piperidine-1-carboxylate (1.81 g) and tetrabutylammonium dihydrogen trifluoride (3.74 g) was stirred at 120° C. overnight. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (960 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][Cl:12])=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>>[Cl:12][CH2:11][C:9]1[O:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=1
Reactant: CCOC(=O)c1cnc(CCl)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc(CCl)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloromethyl-oxazole-5-carboxylic acid ethyl ester (J. Chromatography B, 674, 167, 1995) (190 mg, 1 mmol) and 1N NaOH (2 mL, 2 mmol) is stirred at room temperature for 3 hours then 1N HCl (2 mL, 2 mmol) is added and the solvent is removed under reduced pressure to give the title compound which is used as is in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:20])[CH:14]=2)[N:9]=1
Reactant: NCc1cc2cc(F)ccc2nc1-c1ccccc1Cl
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2nc(-c3ccccc3Cl)c(CNc3ncnc4[nH]cnc34)cc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-6-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=1683 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.44 (s, 1 H), 8.14 (s, 1H), 8.07-8.11 (m, 2H), 7.66-7.71 (m, 1H), 7.59-7.66 (m, 1H), 7.49-7.55 (m, 2H), 7.40-7.46 (m, 1H), 7.34-7.40 (m, 1H), 4.05-4.17 (m, 2H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[C:5]([O:23][C:24]([F:27])([F:26])[F:25])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][N:2]([S:28]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[C:5]([O:23][C:24]([F:25])([F:27])[F:26])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cc(OC(F)(F)F)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.9 %

Procedure:
A mixture of ethyl {2-[7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (300 mg), 1N aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was crystallized from ethyl acetate-hexane to give the title compound (270 mg, yield 93%) as pale-yellow crystals. The crystals were purified by preparative HPLC, and recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 225-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([F:23])[CH:29]=[C:28]([F:30])[CH:27]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Reactant: Fc1cc(F)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2cc1NC(=S)N1CCN(c2cc(F)cc(F)c2)CC1
Yield: 78 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3,5-difluorophenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.Cl[C:16]1[N:21]2[N:22]=[C:23]([CH:25]3[CH2:27][CH2:26]3)[CH:24]=[C:20]2[N:19]=[CH:18][CH:17]=1>CN(C=O)C.CCOC(C)=O>[CH:25]1([C:23]2[CH:24]=[C:20]3[N:19]=[CH:18][CH:17]=[C:16]([S:14][C:11]4[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=4)[N:21]3[N:22]=2)[CH2:27][CH2:26]1
Reactant: Clc1ccnc2cc(C3CC3)nn12
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccnc3cc(C4CC4)nn23)cc1
Temperature: 60 °C

Procedure:
To a mixture of cesium carbonate (0.606 g, 1.86 mmol) and 4-aminobenzenethiol (116 mg, 0.930 mmol) in DMF (3 mL) at RT was added 7-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine (0.180 g, 0.930 mmol). The mixture was heated to 60° C. After 2 hrs the mixture was cooled to RT, diluted with EtOAc, and washed with water and brine. After drying the organic fraction with sodium sulfate, the solvent was removed in vacuo to afford 4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)benzenamine, which was advanced without further purification. MS: Found M+H+=283.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:12]([O-])([O-])OCC>>[S:8]1(=[O:9])(=[O:10])[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[NH:1][CH:12]=[N:11]1
Reactant: CCOC([O-])[O-]
Reactant: Nc1ncccc1S(N)(=O)=O
Product: O=S1(=O)N=CNc2ncccc21

Procedure:
A mixture of 2 g of 2-aminopyridine-3-sulfonamide (Preparation 6) and 20 cm3 of ethyl orthoformate is brought to reflux for 1 hour. After cooling, the crystalline precipitate obtained is collected on a filter and washed with ether.