Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:20]>>[ClH:20].[CH2:1]([O:8][CH:9]1[CH2:10][NH:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)C1
Agent: Cl
Product: c1ccc(COC2CNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
tert-butyl 3-(benzyloxy)azetidine-1-carboxylate 23 (1.0 μm) was taken into a round bottomed flask and was added methanolic-HCl (15 mL, 20%) and was stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum to get a white solid as a crude product. The crude product was washed with ethyl acetate repeatedly and then dried well to obtain compound 24 as a white solid (92%) and was used further without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[C:17]([N:6]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:16])(=[O:20])[CH2:18][CH3:19]
Reactant: CCC(=O)Cl
Reactant: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Product: CCC(=O)N(CCCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-(3-dimethylamino-propylamino)-nitrobenzene and propionylchloride
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl-].[NH4+].[N-:48]=[N+:49]=[N-:50].[Na+]>CN(C=O)C>[C:1]([O:7][CH2:8][C@H:9]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:50][N:49]=[N:48][N:30]=5)[CH:24]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:6])[C:2]([CH3:3])([CH3:5])[CH3:4]
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc(C#N)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3ccnc(-c4cccc(-c5nnn[nH]5)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 120 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-cyanophenyl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (17.2 mg, 0.027 mmol) in DMF (0.5 mL) was added ammonium chloride (7.2 mg, 0.135 mmol) and sodium azide (9.4 mg, 0.144 mmol). The reaction mixture was heated at 120° C. for 6 h then cooled. The crude reaction mixture was passed through a silica gel plug (hexanes/ethyl acetate eluent) to remove the DMF and salts, concentrated, and used without further purification. LCMS-ESI+: calc'd for C37H38ClN6O3S: 681.2 (M+H+); Found: 680.9 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([OH:34])=O)(=[O:30])=[O:29])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:37].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:36]([CH3:37])[CH3:35])=[O:34])(=[O:29])=[O:30])=[N:15][N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)O)s2)cc1C#N
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CC(=O)N(C)C)s2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Prepared using General Procedure 16: To (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid (20 mg, 0.04 mmol) in DCM (0.4 mL) was added HATU (45 mg, 0.12 mmol) and DIEA (10.3 mg, 0.08 mmol). After 30 min, dimethylamine (2M solution in THF, 200 μL, 0.4 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was quenched with water (100 μL) and the solvent evaporated. The crude material was purified by preparative HPLC to afford 14 mg (66%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 43 as white solid. LCMS-ESI (m/z) calculated for C25H27N5O4S2: 525.2; found 526.2 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=8.9, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.50 (d, J=8.2 Hz, 1H), 5.07 (q, J=7.7 Hz, 1H), 4.76 (hept, J=6.1 Hz, 1H), 4.28 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 3.50 (ddd, J=17.0, 8.8, 3.4 Hz, 1H), 3.20 (dt, J=9.7, 7.1 Hz, 1H), 3.15 (s, 3H), 3.02 (s, 3H), 2.72 (dtd, J=11.4, 8.0, 3.5 Hz, 1H), 2.20 (dq, J=13.1, 8.4 Hz, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.99, 165.73, 163.22, 161.71, 144.17, 141.92, 133.44, 133.34, 129.31, 127.92, 127.33, 126.37, 122.70, 115.57, 113.91, 103.71, 72.56, 59.23, 54.92, 38.30, 35.99, 31.36, 21.74. Chiral HPLC: (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide was eluted in 40% IPA in hexanes, 100% ee, tR=22.87 min.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([CH3:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:4]4[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]4(=[O:8])=[O:7])=[CH:11][C:12]=3[CH3:32])=[O:17])[CH2:23][CH2:22]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3C)CC2)c(C)c1
Yield: 17.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (210 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 4, the title compound (42 mg) was obtained.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:2]([CH3:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+]>CC(=O)CC>[NH:1]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH:21]([CH2:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:12]=1)[C:2]([CH3:4])=[O:3]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: CC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC(Oc1ccc(CCNC(C)=O)cc1)C(=O)OCC

Procedure:
A mixture of 17.92 g. (0.1 mol) 4-(2-acetamino-ethyl)-phenol, 17.3 g. (0.125 mol) pulverized potassium carbonate and 150 ml. butan-2-one is stirred for 2 hours at reflux temperature, then 27.9 g. (0.125 mol) ethyl 2-bromohexanoate and a spatula tip of potassium iodide are added thereto and the reaction mixture kept at reflux temperature for a further 28 hours. The reaction mixture is then filtered with suction and the filtrate evaporated in a vacuum. The residue is taken up in diethyl ether and the ethereal phase is extracted with 2 N hydrochloric acid, water, 0.5 N aqueous sodium hydroxide solution and again with water, dried over anhydrous sodium sulphate and evaporated to give 32.1 g. (quantitative yield) ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-n-hexanoate in the form of a colorless oil with a refractive index nD20 =1.5010.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].Cl[CH2:13][O:14][CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH3:9]
Reactant: COCCl
Reactant: Cc1cc(O)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-3-methylphenol (6) (1.0 equiv.) in DMF (0.5 M) at 0° C. was added portionwise 60% wt NaH (1.5 equiv.). The addition was controlled such that internal reaction temperature never went above 10° C. The reaction was stirred at room temperature for 45 minutes, then a solution of chloro(methoxy)methane (1.2 equiv.) in DMF (3M) was added dropwise via additional funnel. The reaction was stirred at room temperature for 3.5 hours, and then quenched by pouring into ice. The resulting mixture was stirred at room temperature for 1 hour. Ether was added, and the two layers were separated. The aqueous layer was extracted (1×) with ether. The combined organic layers were washed with water (2×), brine, dried over MgSO4, and concentrated to give 1-bromo-4-(methoxymethoxy)-2-methylbenzene (7) as a colorless oil. The crude material was used in the next step without further purification.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=1[F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18](N1CCOCC1)=[O:19].Cl>C1COCC1.CC(OC)(C)C>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[O:19])=[CH:12][C:11]=1[F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=CN1CCOCC1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=Cc1ccc(OCc2ccccc2)c(F)c1
Reaction time: 1 h

Procedure:
25.9 g (1.07 mol) of magnesium turnings are initially introduced in 200 ml of THF, and a solution of 285.6 g (1.02 mol) of 1-benzyloxy-4-bromo-2-fluorobenzene in 700 ml of THF is added dropwise at such a rate that a gentle reflux is maintained after initiation of the Grignard reaction. When the addition is complete, the mixture is diluted with 1000 ml of THF, and the batch is heated at the boil for 1 h. The solution of the Grignard reagent is cooled to 0° C., and 118 ml (1.07 mol) of N-formylmorpholine in 100 ml of THF are added dropwise. After 1 h, the mixture is diluted with MTBE and hydrolysed using dilute hydrochloric acid. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with saturated sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product is recrystallised from n-heptane:MTBE.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:58]([C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63])#[CH:59]>CN(C=O)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([C:59]#[C:58][C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63])=[N:7]2
Reactant: Oc1ccc2nccn2n1
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1cccc(C#Cc2ccc3nccn3n2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring mixture of 6-hydroxyimidazo[1,2-b]pyridazine (2.06 g, 15.259 mmol, 1 eq) in anhydrous DMF (20 mL) under nitrogen atmosphere was added triethylamine (8.51 mL, 4 eq) and N-phenyl-bis(trifluoromethanesulfonimide) (5.386 g, 1 eq). After the reaction was stirred at room temperature for 18 hours, to the reaction was added triphenylphosphine (100 mg, 0.025 eq), bis(triphenylphosphine)palladium(II) dichloride (1.07 g, 0.1 eq), copper(I) iodide (581 mg, 0.2 eq), and 3-ethynylaniline (2.394 mL, 1.5 eq) under nitrogen atmosphere. The resulting reaction mixture was heated at 60° C. for two hours. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, the residue mixture was subject to a gradient column chromatography (from DCM to MeOH-DCM 1:25). The product fractions were collected, concentrated, and the residue was triturated with EtOAc-Hex (˜1:5) to give 3-(imidazo[1,2-b]pyridazin-6-ylethynyl)aniline as a fluffy slightly yellow solid upon filtration in amount of 2.384 g (67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)O)=[CH:9][N:10]=2)[N:7]=1.II.O[PH2]=O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[CH:9][N:10]=2)[N:7]=1
Reactant: OC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: II
Agent: O=[PH2]O
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc2ncccc2c(F)c1Cc1cnc2ccc(Cl)nn12
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(5,7-difluoro-quinolin-6-yl)-methanol (Stage 171.3, 200 mg, 0.577 mmol) was dissolved in acetic acid (4.93 mL) and introduced in a microwave reactor together with iodine (439 mg, 1.731 mmol) and H3PO2 (0.47 mL of a 50% aqueous solution, 8.65 mmol). The RM was stirred under microwave irradiations at 150° C. for 5 min. It was basified by a 2.5 M NaOH solution and extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed to afford the title compound as a beige solid (tR 1.0 min (conditions 2), MH+=331).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)nc1

Procedure:
To a mixture of the amidine of step 1 (10 mmol and sodium bicarbonate (20 mmol) in isopropanol (150 ml), 3-bromo-1,1,1-trifluoroacetone (15 mmol) is added. After heating at 80°-85° C. for 24 hours, the reaction mixture is cooled and filtered. The residue is washed with methylene chloride and the combined organic fractions are dried over sodium sulfate, filtered and concentrated. The crude mixture is chromatographed on silica gel using mixtures of ethyl acetate, isopropanol and ammonium hydroxide as eluants to give the desired 4,5-dihydro-imidazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Si:10]([O:27][CH2:28][C@H:29]1[CH2:34][O:33][CH2:32][C:31](=[O:35])[N:30]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[Si:10]([O:27][CH2:28][C@H:29]([NH:30][C:36](=[O:37])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:34][O:33][CH2:32][C:31]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:35])([C:23]([CH3:26])([CH3:25])[CH3:24])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1ccc(Cl)cc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
4-Chlorophenylmagnesium bromide (1 M solution in diethyl ether, 3.44 mL) was added dropwise to a solution of tert-butyl (R)-3-(tert-butyldiphenylsilanyloxymethyl)-5-oxomorpholine-4-carboxylate (1.47 g) in THF (35 mL) at −50° C. over five minutes, and the reaction solution was stirred at −40° C. for one hour. A saturated ammonium chloride solution was added to the solution in small portions at −40° C., and the reaction solution was returned to room temperature. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 1.48 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].Cl[C:20]1([C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=2[O:38][CH3:39])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30]>>[Cl:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:30])[C:20]2([N:10]1[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:6][CH:5]1[C:3]([N:2]([CH3:18])[CH3:1])=[O:4])[C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[O:38][CH3:39]
Reactant: CN(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc(C)cc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(C)cc1C1(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Yield: 43.5 %

Procedure:
With 2.43 g of the compound obtained in Step 109-3 and 2.43 g of the compound obtained in Step 109-4 as starting materials, 1.78 g of the title compound was obtained by a similar method to Step 4-2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2=[N:12][N:13]([CH2:30][CH3:31])[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1[N:13]([CH2:30][CH3:31])[N:12]=[C:11]2[C:10]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:3]=[C:2]2[NH2:1]
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCN
Temperature: 25 °C
Yield: 87.2 %

Procedure:
2-[4-(4-Amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]isoindole-1,3-dione (prepared as described in Example 22, 7.10 g, 17.2 mmol), hydrazine hydrate (4.20 mL, 85.9 mmol), and ethanol (213 mL) were combined and heated at reflux for 30 minutes. The solution was allowed to cool to ambient temperature, then was cooled to 0° C. A white solid precipitated from the solution and was isolated by filtration and washed with ethanol. The crude product was purified by chromatography on a HORIZON HPFC system (silica, gradient elution with 10%-75% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to afford 4.25 g of 1-(4-aminobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[C:22](OCC)(=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.5 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (14.2 g) in tetrahydrofuran (400 mL) was slowly added a 1.6M n-butyllithium hexane solution (62 mL) at −78° C. The reaction mixture was stirred for 30 min, diethyl oxalate (16.5 g) was added, and the mixture was further stirred for 2 hr. The reaction mixture was warmed to room temperature, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (12.2 g, yield 52%) was obtained as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 258 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:43]=[CH:42][C:12]3[N:13]([CH2:38][CH:39]4[CH2:41][CH2:40]4)[C:14]([CH2:16][O:17][CH2:18][C:19]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:15][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O)=O>C(OCC)(=O)C>[CH:39]1([CH2:38][N:13]2[C:12]3[CH:42]=[CH:43][C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)=[CH:10][C:11]=3[N:15]=[C:14]2[CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Agent: C=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CN1CCC(COCc2nc3cc(-c4ccc(C#N)cc4)ccc3n2CC2CC2)(c2ccccc2)CC1
Temperature: 70 °C
Yield: 50 %

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-1-(cyclopropylmethyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (23 mg, 0.04 mmol) was combined with aqueous formaldehyde (37%, 0.5 mL, 168 equiv) and formic acid (0.5 mL, 329 equiv) and heated at 70° C. for 64 h. At the end, after adjusting the pH of the reaction mixture to 6.0 extractive work up with ethyl acetate followed by evaporation of the organic layer in vacuo gave the crude product. The crude product was purified by preparative HPLC (HPLC method 12). Fractions containing the required product were combined and evaporated in vacuo. The residue obtained was purified by silica gel chromatography using a linear gradient of 1.2%-20% methanol in dichloromethane to obtain 12 mg (50% yield) as a TFA salt. 1H-NMR (500 MHz, CD3OD) δ 7.92 (s, 1H), 7.86 (d, JAB=8.5 Hz, 2 H), 7.81 (d, JAB=8.5 Hz, 2 H), 7.67-7.65 (m, 1 H), 7.63 (d, J=8.2 Hz, 1 H), 7.39-7.32 (m, 4 H), 7.24 (m, 1 H), 4.75 (s, 2 H), 3.84 (d, J=6.7 Hz, 2 H), 3.60 (s, 2 H), 3.08 (m, 2 H), 2.67 (m, 2 H), 2.55 (s, 3 H), 2.42 (m, 2 H), 2.12 (m, 2 H), 1.05 (m, 1 H), 0.51-0.48 (m, 2 H), 0.35-0.32 (m, 2 H). 13C NMR (126 MHz, CD3OD) δ 151.8, 146.5, 142.2, 136.1, 134.4, 132.8, 128.8, 128.0, 127.2, 126.8, 123.0, 118.9, 117.6, 111.6, 110.4, 65.5, 51.5, 43.7, 40.4, 30.6, 11.0, 3.6. Mass Spec.: 491(MH)+.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:12](C(Br)C(=O)C3[C:10]=2[C:5]2[C:6](C(C(Br)C(=O)[C:4]=2[CH:3]=1)=O)=CC=3)=[O:13].O1CC1>>[CH2:12]([OH:13])[CH2:11][CH2:2][CH2:3][CH2:4][CH:5]([CH3:10])[CH3:6]
Reactant: O=C1c2ccc3c4c(ccc(c24)C(=O)C1Br)C(=O)C(Br)C3=O
Agent: Cl
Solvent: C1CO1
Product: CC(C)CCCCCO

Procedure:
Using the same screening procedure, 40 ml. of 15 wt. % HCl was mixed with 5 ml. of a phosphate ester surfactant sold under the trade name Klearfac AA-420 by BASF Wyandotte Corporation and identified (see Toxic Substances Control Act (TSCA) Chemical Substance Inventory, vol III, "User Guide and Indices to the Initial Inventory; Substance Name Index", May 1979) as oxirane, methyl-, polymer with oxirane, mono-C12 -C18 -alkyl ethers, phosphates consistent with the formulas (1) and (2). A clear solution with slight foam resulted. The first three additions of 1 ml. aliquots of isooctyl alcohol were solubilized resulting in a clear solution. The fourth ml. produced a hazy stable mixture and the fifth a stable emulsion. After a total of 5 ml. of isooctyl alcohol added and fifteen minutes of standing, 1 ml. of clear oil separated on top. The performance of this phosphate ester surfactant appears superior to other surfactants previously tested.