Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Yield: 99 %

Procedure:
A solution of 2,6-dichloro-4-iodobenzoic acid (5.50 g, 17.4 mmol) in thionyl chloride (52 mL) was heated under reflux for 2 hours then diluted with toluene and concentrated under reduced pressure. The resultant residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired compound as a yellow oil (5.75 g, 99% yield). 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[O:3][C:4](=[O:19])[NH:5][CH2:6][C:7](=[O:18])[NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][CH2:11][S:12][CH3:13].[NH2:22][OH:23]>O1CCOCC1>[OH:23][NH:22][C:14](=[O:15])[C@@H:9]([NH:8][C:7](=[O:18])[CH2:6][NH:5][C:4](=[O:19])[O:3][C:2]([CH3:21])([CH3:20])[CH3:1])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: NO
Reactant: COC(=O)[C@H](CCSC)NC(=O)CNC(=O)OC(C)(C)C
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)NO
Yield: 28 %

Procedure:
A solution of (S)-methyl 12,12-dimethyl-7,10-dioxo-11-oxa-2-thia-6,9-diazatridecane-5-carboxylate (7 g, 21 mmol) in dioxane (120 mL) and hydroxylamine (50% in water, 80 mL) was stirred at room temperature for 4 hours. The solution was concentrated and extracted with ethyl acetate (200 mL). The organic layers were washed with 1N HCl, brine, and dried over sodium sulfate, filtered and concentrated to give a residue, which was purified on silica gel column (hexane:ethyl acetate, 1:1 to pure acetate) to give (S)-tert-butyl 2-(1-(hydroxyamino)-4-(methylthio)-1-oxobutan-2-ylamino)-2-oxoethylcarbamate (2 g, 28%). MS calcd for (C12H23N3O5S+H)+: 322.1; MS found: (M+H)+=322.0.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[S:4]1[C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:16][CH2:17]2)=[CH:6][N:7]=[CH:3]1
Reactant: C[Si](C)(C)c1ncc(C2(O)CCC3(CC2)OCCO3)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OC1(c2cncs2)CCC2(CC1)OCCO2

Procedure:
The title compound was prepared as white solid from 8-(2-trimethylsilanyl-thiazol-5-yl)-1,4-dioxa-spiro[4.5]decan-8-ol followed by TBAF work-up.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]([OH:19])=O)=[C:8]([C:13]([F:16])([F:15])[F:14])[N:9]2[CH3:12])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:17]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH3:12])[C:8]=1[C:13]([F:16])([F:15])[F:14])=[O:19]
Reactant: CN
Reactant: COc1ccc2c(C(=O)O)c(C(F)(F)F)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: CNC(=O)c1c(C(F)(F)F)n(C)c2cc(OC)ccc12
Yield: 98 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-2-trifluoromethyl-1H-indole-3-carboxylic acid 76f (880 mg, 3.22 mmole), oxalyl chloride (3 ml, 2.0M solution) and methylamine (5 ml, 2.0M solution) in a manner as previously described for example 16d to give 900 mg product as white solid (98% yield). 1H NMR (300 MHz, CDCl3) δ 7.62 (1H, d, J=8.9 Hz), 6.88 (1H, dd, J=2.1, 8.9 Hz), 6.73 (1H, d, J=2.1 Hz), 5.80 (1H, bs), 3.88 (3H, s), 3.79 (3H, s), 3.04 (3H, d, J=4.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].C(O)(=O)C.[CH:25](N)=[NH:26]>C(N)=O.CCOC(C)=O>[OH:8][C:7]1[C:6]2[C:5]3[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:15][C:4]=3[S:3][C:2]=2[N:1]=[CH:25][N:26]=1
Reactant: N=CN
Reactant: CCOC(=O)c1c(N)sc2c1CC(C(=O)OCC)CC2
Solvent: NC=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2sc3ncnc(O)c3c2C1
Temperature: 180 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
A solution of 3,5-diethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3,5-dicarboxylate (8 g, 26.90 mmol, 1.00 equiv) in formamide (150 mL) was added formamidine acetate (10 g, 96.05 mmol, 3.57 equiv) at room temperature under nitrogen. The resulting solution was stirred for 4 h at 180° C. After cooling, the resulting solution was diluted with 200 mL of EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) give the desired ethyl 4-hydroxy-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine-6-carboxylate (4.1 g, 55%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[CH3:6])[CH3:2].[NH:22]([C:35]([O:37][CH2:38][CH:39]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])[C@H:23]([C:32](O)=[O:33])[CH2:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH:41]1[C:40]2[CH:39]([CH2:38][O:37][C:35]([NH:22][C@H:23]([C:32]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:19][CH2:20][CH3:21])[O:3][CH2:1][CH3:2])[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18]=3[N:17]=[CH:16][CH:15]=[CH:14]4)=[O:33])[CH2:24][C:25]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:31])=[O:36])[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]=2[CH:44]=[CH:43][CH:42]=1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-3) 13.0 g (45 mmol) and Fmoc-Asp(tBu)-OH 24.2 g (58.8 mmol) were dissolved in DMF (200 ml). HATU (25.6 g, 67.5 mmol) and DIEA (8.7 g, 67.5 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was poured into water (800 ml). The solution was extracted with EA (300 ml×3). The combined extracts were dried over Na2SO4 and then filtered. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel with PE:EA=30:1 to 5:1 to give the title compound 20.6 g, (yield 67%).
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[C:7](=[O:9])[N:8]=1.[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>C(O)C>[F:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:12]=[N:13][CH:14]=[N:15][CH:16]=4)[C:7](=[O:9])[N:8]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: O=c1nc(NCCc2ccc(Oc3ccc(F)cc3)cc2)[nH]cc1Cc1cncnc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
2-Methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (30 mg, 0.128 mmol, 1 eq) and 2-[4-(4-Fluoro-phenoxy)-phenyl]-ethylamine (44.4 mg, 0.192 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 125° C. for overnight. Reaction mixture was evaporated and crude residue was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-{2-[4-(4-fluoro-phenoxy)-phenyl]-ethylamino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.068 mmol; yield: 53.1%, HPLC-MS/UV: [M+H]+=418.45; rt: 9.78 min; purity: 98%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.75 (t, J=7.50 Hz, 2H), 3.39-3.49 (m, 2H), 3.51 (s, 2H), 6.46 (br.s, 1H), 6.90 (d, J=8.57 Hz, 2H), 6.97-7.05 (m 2H), 7.15-7.25 (m, 4H), 7.66 (s, 1H), 8.66 (s, 2H), 8.97 (s, 1H), 10.92 (br.s., 1H)
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=[O:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br>C1COCC1>[C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:26])[CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a solution of 1-trityl-1H-imidazole-4-carbaldehyde (10.0 g, 0.03 mol) in anhydrous THF (100 mL) was added dropwise methyl magnesium bromide (1.4 M in hexane, 52.8 mL, 0.075 mol) at 0° C. After the addition, the mixture was stirred at RT overnight. The reaction was quenched with sat. aq. NH4Cl (50 mL) and the mixture extracted with CH2Cl2 (3×50 mL). The organic layers were combined, washed with 1 N aq. NaOH (3×20 mL), water (3×20 mL) and brine (100 mL), dried over MgSO4 and evaporated. The residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:5) to yield the title compound (8.0 g, 75.0%) as a white solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[CH3:35][O:34][CH2:33][CH2:32][C:31]1[N:36]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:23])[F:24])[CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCOCC2)C1
Product: COCCc1noc(C2CC(c3cccc(OC(F)(F)F)c3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 201A and 117 mg (0.75 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 106 mg (44% of theory)
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cccc(Cl)c2)s1
Yield: 26 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-chlorophenylboronic acid (9 mg, 0.06 mmol). The title compound was obtained in 26% yield (5.4 mg). MS (ESI+) calcd mass for C17H12ClN5O2S2 417.012094, found 417.012844.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:9][C:10]([CH2:15][CH2:16][CH3:17])(CO)[CH2:11][OH:12]>CCCCCCC>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][C:7]=1[C:10]([CH2:11][OH:12])([CH3:9])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(C)(CO)CO
Reactant: Clc1ccc(Cl)nn1
Solvent: CCCCCCC
Product: CCCC(C)(CO)c1cc(Cl)nnc1Cl

Procedure:
Twenty g. of 3,6-dichloropyridazine was alkylated with 44.4 g. of 2-methyl-2-propyl-1,3-propanediol, following the process of Preparation 3 above. In this case the chromatography was run with 3:1 heptane:ethyl acetate as the eluant, and the residue from evaporation of the combined product-containing fractions was recrystallized from diethyl ether/heptane to obtain 0.43 g. of the desired intermediate product, m.p. 99°-100°.
Reaction SMILES: [CH:1]12[C:7](=[O:8])[NH:6][CH:5]1[CH2:4][CH2:3][CH2:2]2.O1CCCC1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(OCC)(=O)C.O>[Cl:21][CH2:22][C:23]([N:6]1[C:7](=[O:8])[CH:1]2[CH:5]1[CH2:4][CH2:3][CH2:2]2)=[O:24]
Reactant: O=C1NC2CCCC12
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CCl)N1C(=O)C2CCCC21
Temperature: 3 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
In a four-necked flask with a volume of 300 mL, which was equipped with a thermometer, a stirrer, a dropping funnel, and a nitrogen introducing tube, 11.1 g (100 mmol) of 6-azabicyclo[3.2.0]heptan-7-one, 100 mL of tetrahydrofuran, and 12.1 g (120 mmol) of triethylamine were charged, and an internal temperature was cooled to 3° C. 12.4 g (110 mmol) of 2-chloroacetyl chloride was added dropwise at that temperature over 15 minutes from the dropping funnel. After completion of the dropwise addition, the mixture was stirred for 3 hours. Thereafter, 50 mL of water and 50 mL of ethyl acetate were added, and a liquid separation operation was carried out. The obtained organic layer was concentrated under reduced pressure, thereby obtaining 8.4 g (45 mmol) of 6-chloroacetyl-6-azabicyclo[3.2.0]heptan-7-one having the following properties.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[N:10](C(OC(C)(C)C)=O)[C:11]3[C:16]([C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:14]([C:24](=[O:35])[NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1>Cl.O1CCOCC1>[O:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][CH2:26][NH:25][C:24]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=2)=[C:17]3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:35])[CH2:34][CH2:33]1
Reactant: COc1ncccc1-c1c(-c2ccccc2)c2cc(C(=O)NCCCN3CCOCC3)ccc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCCCN1CCOCC1)c1ccc2[nH]c(-c3ccc[nH]c3=O)c(-c3ccccc3)c2c1

Procedure:
A solution of tert-butyl 2-(2-methoxypyridin-3-yl)-5-(3-morpholinopropylcarbamoyl)-3-phenyl-1H-indole-1-carboxylate (0.23 mmol) in 4 N HCl in dioxane (10 ml) was shaken at 70° C. overnight. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in dichloromethane (20 ml) and aqueous NaHCO3 (15 ml). The dichloromethane layer was separated, dried using Na2SO4, filtered and concentrated to give a crude product. The crude product was purified by reverse phase HPLC using TFA as a modifier. The desired product was obtained as yellow solid (0.129 g, 78%); 400 MHz 1H NMR (DMSO-d6) δ: 12.137 (s, 1H), 11.79 (s, 1H), 10.78 (bs, 1H), 8.58 (t, J=5.6, 1H), 8.02 (s, 1H), 7.83-7.63 (m, 1H), 7.61-7.26 (m, 8H), 6.15 (t, J=6.7 Hz, 1H), 5.81-5.71 (m, 1H), 4.01-3.61 (m, 5H), 3.61-3.25 (m, 5H), 3.21-2.94 (m, 4H), 2.04-1.87 (m, 2H); LCMS: 456 [M+H].
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:25]4[C:21](=[N:22][O:23][N:24]=4)[CH:20]=[CH:19][C:18]=3[OH:26])[C:9]2=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)ccc2nonc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2c(O)ccc3nonc23)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one (21.8 g, 48.5 mmol), triethylsilane (50 mL) and trifluoroacetic acid (100 mL) was stirred at ambient temperature for 16 h, then heated to 45° C. for 1.5 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated with diethyl ether to afford 1-(diphenylmethyl)-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one (10.94 g, 52%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ10.90-10.00 (br s, 1H), 7.61-7.31 (m, 10H), 7.18 (s, 1H), 7.06-6.89 (m, 4H), 6.55 (d, J=8.4 Hz, 1H), 6.45 (d, J=9.6 Hz, 1H), 5.57 (s, 1H); MS (ES+) m/z 456.0 (M+23).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][C:9](O)=[O:10])[CH2:4][C:5](O)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(C)C.Cl>C1COCC1.C(O)(C)C.O>[F:1][C:2]([F:12])([F:13])[CH:3]([CH2:8][CH2:9][OH:10])[CH2:4][CH2:5][OH:6]
Reactant: O=C(O)CC(CC(=O)O)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: OCCC(CCO)C(F)(F)F
Temperature: 25 °C

Procedure:
12.0 g (59.97 mmol) of 3-(trifluoromethyl)pentanedioic acid were dissolved in 70 ml of abs. THF, and, after cooling to −10° C., 120 ml (120 mmol) of a 1 M solution of lithium aluminium hydride in THF were added dropwise. After the addition had ended, the reaction mixture was warmed to RT overnight. After cooling to 0° C., initially about 10 ml of isopropanol and then 20 ml of an isopropanol/water mixture (3:1) were carefully added dropwise. The resulting suspension was acidified by addition of 1 N hydrochloric acid and mixed with Celite. The mixture was filtered and the filtrate obtained was concentrated under reduced pressure. To remove residual water, acetonitrile was added to the oil obtained and the mixture was once more concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1→1:1). This gave 4.5 g of the target product (43.6% of theory).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[CH:10][CH:11]=1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: COC
Agent: CS(=O)(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(OCC(=O)OCc2ccccc2)c2ccc(N(C)C)cc2)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), benzyl glycolate (6.6 g, 0.039 mole), 90 ml of tetrahydrofuran, 200 ml of hexane, and 10 drops of methanesulfonic acid was refluxed for 6 hours, replacing solvent as distillate was removed; then, 10 drops of tetramethylguanidine was added to discharge the color and the reaction mixture was filtered hot and cooled. A white solid formed which was filtered, washed with petroleum ether and then recrystallized from 4/1 hexane/acetone. The resulting white crystalline product had a mp 101.8°-103° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:8].[Cl:9][CH2:10][C:11]1[C:16]([CH3:17])=[C:15]([S:18][CH2:19][CH2:20][CH2:21][Cl:22])[CH:14]=[CH:13][N:12]=1>C(O)(C)C>[ClH:9].[ClH:8].[Cl:22][CH2:21][CH2:20][CH2:19][S:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([CH2:10][S:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[C:16]=1[CH3:17]
Reactant: Cc1c(SCCCCl)ccnc1CCl
Reactant: Sc1ccccn1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c(SCCCCl)ccnc1CSc1ccccn1

Procedure:
2-Mercaptopyridine (10 mmol) and 2-chloromethyl-4-(3-chloropropylthio)-3-methylpyridine hydrochloride (10 mmol) are heated to boiling in isopropanol (25 ml) for 4-6 h. After cooling, the precipitated solid is filtered off, washed with isopropanol and dried in vacuo at 40° C. 3.6 g (91% of theory) of the title compound are obtained as a colorless solid; m.p. 112-114° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[CH2:17][OH:18])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+]>C(Cl)Cl>[OH:18][CH2:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=1[N:8]=[C:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: COc1ccc(Nc2ccc(O)cc2)c(CO)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: COc1ccc(N=C2C=CC(=O)C=C2)c(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a suspension of 3.7 g of 2-(4-hydroxyphenylamino)-5- methoxybenzenemethanol (Example 1c) in 300 ml of methylene dichloride was added 32 g of silica treated sodium metaperiodate. The reaction mixture was stirred for two hours at room temperature, then filtered and washed with water and dried over anhydrous sodium sulfate. The solution was concentrated and the residue triturated with hexane to give 1.1 g of 4-(2-hydroxymethyl-4-methoxyphenylimino)-2,5-cyclohexadien-1-one, m.p. 87°-89° C.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[C:14]([O:15]C)=[N:13][C:12]2[C:7](=[CH:8][C:9]([N+:30]([O-:32])=[O:31])=[CH:10][C:11]=2[CH2:17][N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:19][C:20]([OH:22])=[O:21])[N:6]=1.[BrH:33]>C(O)(=O)C.C(OCC)C>[BrH:33].[BrH:33].[O:4]=[C:5]1[C:14](=[O:15])[NH:13][C:12]2[C:7](=[CH:8][C:9]([N+:30]([O-:32])=[O:31])=[CH:10][C:11]=2[CH2:17][N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:19][C:20]([OH:22])=[O:21])[NH:6]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN(CC(=O)O)Cc3ccccn3)c2nc1OC
Agent: Br
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
49 mg (0.1 mmol) of N-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-N-(2-pyridylmethyl)-glycine dihydrochloride are stirred in 2 ml of a 48% solution of hydrogen bromide in acetic acid for 18 hours at 70° C. The mixture is diluted with diethyl ether and the solid is filtered off, washed with diethyl ether and dried. The title compound is obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:17])OCC)=[CH:8][C:7]=1[S:18][CH2:19][CH3:20].[CH3:25][O:26][CH:27]([O:31][CH3:32])[CH2:28][NH:29][CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:29]([CH2:28][CH:27]([O:31][CH3:32])[O:26][CH3:25])[CH3:30])=[O:17])=[CH:8][C:7]=1[S:18][CH2:19][CH3:20]
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)Nc1ccc(Oc2ccc(Cl)c(Cl)c2)c(SCC)c1
Solvent: Cc1ccccc1
Product: CCSc1cc(NC(=O)N(C)CC(OC)OC)ccc1Oc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl [4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4-(3,4-dichlorophenoxy)-3-(ethylthio)phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.