Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:19]1[CH2:23][CH2:22][O:21][CH2:20]1>CN(C=O)C.C(Cl)Cl>[O:21]1[CH2:22][CH2:23][CH:19]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[CH2:20]1
Reactant: IC1CCOC1
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC2CCOC2)cc1
Reaction time: 16 h
Yield: 85.6 %

Procedure:
To a suspension of methyl 4-sulfanylbenzoate (0.85 g, 5.05 mmol), potassium carbonate (1.39 g, 10.1 mmol) in DMF (10 mL) at room temperature was added 3-iodotetrahydrofuran (1.00 g, 5.05 mmol). The resulting suspension was stirred for 16 hours. The reaction mixture was diluted with DCM (25 mL), filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM (25 mL) and washed with water (3×15 mL) and saturated aqueous brine solution (1×15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield methyl 4-tetrahydrofuran-3-ylsulfanylbenzoate (1.03 g, 86%) as a yellow solid. ESI-MS m/z calc. 238.1. Found 239.3 (M+1)+; Retention time: 1.47 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.91-7.83 (m, 2H), 7.48-7.39 (m, 2H), 4.16-4.08 (m, 2H), 3.91-3.72 (m, 5H), 3.55 (q, J=7.6 Hz, 1H), 2.49-2.35 (m, 1H), 1.86-1.74 (m, 1H).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[C:15](/[CH:17]=[C:18](/[N+:20]([O-:22])=[O:21])\[CH3:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C.C1COCC1>[CH2:3]([O:10][C:11]1[CH:16]=[C:15]([CH2:17][CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])[CH:14]=[CH:13][C:12]=1[O:23][CH3:24])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc(/C=C(\C)[N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CC(C)[N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
To a suspension of sodium borohydride (1.52 g, 40 mmol) in ethanol (20 ml) at 0° C. was added a solution of 208 (6 g, 20 mmol) in THF (40 ml). The addition was over 20 min, the reaction mixture was stirred for 1 h at 0° C. and at rt for 30 min. 2M HCl (20 ml) was added (care—vigorous reaction!) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×60 ml). The combined organic layers were washed with water (60 ml) and brine (60 ml), dried (MgSO4) and concentrated in vacuo to afford the crude material as an orange oil. Purification by flash column chromatography eluting with hex:EtOAc; 4:1 afforded the title compound (3.35 g, 55%) as a pale green solid. 1H NMR (270 MHz; CDCl3) 1.44 (3H, d, J=6.7 Hz, CH3), 2.87 (1H, dd, J=14.1, 6.9 Hz, one of CH2), 3.19 (1H, dd, J 14.1, 7.4 Hz, one of CH2), 3.85 (3H, s, OCH3), 4.65 (1H, sext, J=6.9 Hz, CH), 5.12 (2H, s, CH2Ph), 6.65-6.71 (2H, m, 2×CH), 6.81 (1H, d, J=8.2 Hz, CH), 7.25-7.43 (5H, m, 5×CH). 13C NMR (67.5 MHz; CDCl3) 18.71 (CH3), 40.80 (CH2), 56.08 (OCH3), 71.17 (CH2), 84.64 (CH), 112.0 (CH), 115.15 (CH), 121.93 (CH), 127.47 (CH), 127.87 (C), 128.0 (CH), 128.67 (CH), 136.99 (C), 148.14 (C), 149.13 (C), LC/MS (APCI−) tr=1.1 min, m/z 300.01 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[Li+].[CH3:36][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:11](=[O:32])[CH:10]([CH3:36])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)CC[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CN2C(=O)C(C)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one (Example 71, Step A) (140.34 g, 298 mmol) in anhydrous THF (994 mL) was degassed by bubbling argon through the solution for 20 minutes while it cooled to −78° C. Iodomethane (23.32 mL, 373 mmol) was added followed by the addition of LHMDS (328 mL, 328 mmol) over 15 minutes. The reaction mixture was stirred for 15 minutes at −78° C. and then the reaction was removed from the cold bath and stirred at rt for 12 hours. The reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL) and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide an orange oil. Purification (wet loaded with small amount of DCM) using the Combiflash Companion XL (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 1.5 kg SiO2 column and eluting with 4 L each of 15-20-25-30-35% EtOAc/hexanes provided the title compound as a thick very pale yellow oil and a 3.7:1 mixture of C-3 diastereomers.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=CC=C[CH:2]=1.[C:9]1([OH:15])C=CC=[CH:11][CH:10]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][Si](OC)(OC)OC)[CH:17]1[O:19][CH2:18]1.[SiH4]>C(C(C)=O)C>[C:6]([O:7][CH2:11][CH:10]1[O:15][CH2:9]1)(=[O:19])[C:1]([CH3:8])=[CH2:2].[C:21]([O:20][CH2:16][CH:17]1[O:19][CH2:18]1)(=[O:7])[CH:22]=[CH2:23]
Reactant: Oc1ccccc1
Reactant: CO[Si](CCCOCC1CO1)(OC)OC
Reactant: Cc1ccccc1O
Agent: [SiH4]
Solvent: CCC(C)=O
Product: C=C(C)C(=O)OCC1CO1
Product: C=CC(=O)OCC1CO1

Procedure:
Methyl ethyl ketone was added to a composition comprising 45 parts by weight of a bisphenol A epoxy resin (epoxy equivalent weight: 190, trade name: EPIKOTE 828 produced by Yuka Shell Epoxy Co., Ltd.) and 15 parts by weight of a cresol novolac epoxy resin (epoxy equivalent weight: 195, trade name: ESCN 195 produced by Sumitomo Chemical Co., Ltd.) as epoxy resins, 40 parts by weight of a phenol novolac resin (trade name: PLYORPHEN LF2882 produced by Dainippon Ink & Chemicals, Inc.) as a hardener for the epoxy resins and 0.7 parts by weight of γ-glycidoxypropyltrimethoxysilane (trade name: NUCA-187 produced by Nippon Yunicar Kabushiki Kaisha) as a silane coupling agent and mixed with stirring. To the mixture were added 150 parts by weight of an epoxidized acrylic copolymer having a glycidyl methacrylate or glycidyl acrylate unit content of 2 to 6 wt. % (weight average molecular weight: 1,000,000, trade name: HTR-860P-3 produced by Teikoku Kagaku Sangyo Co., Ltd.) and 4 parts by weight of an amine-epoxy adduct (trade name: AMICURE MY-24 produced by Ajinomoto Co., Inc.) as a curing accelerator, and the mixture was stirred with an agitating motor for 30 minutes, to obtain a varnish. A 75 μm-thick coating of a B-stage state was formed from the varnish, to produce an adhesive film bearing a carrier film (a release treated polyethyleneterephthalate film, thickness: 75 μm) (drying conditions: temperature: 140° C., time: 5 minutes). In the adhesive of the B-stage state, AMICURE MY-24 was dissolved uniformly in the mixture of the epoxy resins and hardener, but was not dissolved in the acrylic rubber and was deposited as particles. After the complete curing of the adhesive, the epoxy resins and the acrylic rubber were separated into a disperse phase and a continuous phase, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([O-:34])=[O:33])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].[CH2:35](N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[CH2:27][CH:28]3[C:32]([O:34][CH3:35])=[O:33])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(C(=O)[O-])C1
Reactant: CCN(CC)CC
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (1.6 g) in dichloromethane (15 ml) is added dropwise, at 0° C. taking 3 minutes, to a mixture of 4-tert-butoxycarbonylpiperazine-2-carboxylate (1.8 g) obtained in Reference Example 16, triethylamine (1.3 g) and dichloromethane (20 ml). The reaction mixture is poured into water and extracted with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=5:4:1) to afford methyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-tert-butoxycarbonylpiperazine-2-carboxylate as a colorless oily product (2.8 g).
Reaction SMILES: [CH:1]([N:4]1[C:11]2[C@@H:10]3[CH2:12][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[C:16]1([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][C:22]([NH:25][C:13]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:12][C@H:10]3[C:11]=2[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=1)=[O:15])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:24]
Reactant: CC(C)n1nc(C(=O)O)c2c1[C@@H]1C[C@@H]1C2
Reactant: CC(C)(N)c1ccccc1
Product: CC(C)n1nc(C(=O)NC(C)(C)c2ccccc2)c2c1[C@@H]1C[C@@H]1C2

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-Isopropyl-1a,2,5,5a-tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid and 2-phenylpropan-2-amine. LCMS m/z=324.6 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][C:15](=[O:17])[NH2:16])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CC(C)=O
Product: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
To a solution of 0.700 g. of N-benzyloxycarbonyl-L-glutamine, 0.665 g. of pentachlorophenol and 0.55 g. of 2,2'-dipyridyl disulfide in 20 ml. of dry acetone is added an acetone solution of 0.655 g. of triphenyl phosphine with stirring at 0°C. The produced precipitates are recovered by filtration and washed successively with a 3 % sodium bicarbonate solution, water and ether and recrystallized from a mixture of dimethylformamide and methanol to give 0.952 g. of the desired product.
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][C:14](F)=[CH:15][CH:16]=[C:11]2[C:10]([CH2:18][O:19][C:20]2[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[C:22]([O:28][C:29]3[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[C:31]([Cl:37])[CH:30]=3)[CH:21]=2)=[N:9]1)=O)(C)(C)C.COC1C=CC(C[NH2:45])=CC=1>CN1C(=O)CCC1.CCOC(C)=O.C(O)(C(F)(F)F)=O>[NH2:45][C:14]1[N:13]=[C:12]2[NH:8][N:9]=[C:10]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[C:22]([CH:21]=3)[O:28][C:29]3[CH:34]=[C:33]([CH:32]=[C:31]([Cl:37])[CH:30]=3)[C:35]#[N:36])[C:11]2=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)n1nc(COc2cc(F)c(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ccc(F)nc21
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2cc(OCc3n[nH]c4nc(N)ccc34)cc(F)c2Cl)c1
Temperature: 95 °C
Yield: 4.3 %

Procedure:
Under a nitrogen atmosphere, tert-butyl3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)-5-fluorophenoxy]methyl}-6-fluoro-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (50-6) (230 mg, 0.420 mmol) was dissolved in NMP (4 mL, 0.1 M). Next, 4-methoxybenzylamine (288 mg, 2.101 mmol) was added and the reaction was heated to 95° C. for 2 hours. It was then diluted with EtOAc (4 mL). It was partitioned with water (3 mL) and then extracted with EtOAc (3×4 mL). The organic extracts were then washed with water (3×4 mL) and brine (1×4 mL), dried over sodium sulfate and concentrated. The crude reaction material was then diluted with TFA (3 mL) and heated to 65° C. for 2 hours. It was then concentrated and purified on a reverse phase system (5%-95% AcCN/H2O with 0.5% TFA) to give 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methoxy]-2-chloro-3-fluorophenoxy}-5-chlorobenzonitrile (50-7) (8 mg, 4%). LCMS (ES) m/z 445.9 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:20][C:21]1([CH3:46])[C:30]([CH3:31])=[CH:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:32]3[CH2:38][C:37]4[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:36]=4[O:35][CH2:34][CH2:33]3)[C:23]=2[CH2:22]1>>[NH2:1][C:2]1[C:7]([S:8]([NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14]2)(=[O:10])=[O:9])=[CH:6][C:5]([C:40]2[CH:41]=[CH:42][C:36]3[O:35][CH2:34][CH2:33][N:32]([C:24]4[C:23]5[CH2:22][C:21]([CH3:20])([CH3:46])[C:30]([CH3:31])=[CH:29][C:28]=5[N:27]=[CH:26][N:25]=4)[CH2:38][C:37]=3[CH:39]=2)=[CH:4][N:3]=1
Reactant: CN1CC[C@H](CNS(=O)(=O)c2cc(Br)cnc2N)C1
Reactant: CC1=Cc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2CC1(C)C
Product: CC1=Cc2ncnc(N3CCOc4ccc(-c5cnc(N)c(S(=O)(=O)NC[C@H]6CCN(C)C6)c5)cc4C3)c2CC1(C)C

Procedure:
Prepared according to the method of 5 by using 2-amino-5-bromo-N-{[(3S)-1-methylpyrrolidin-3-yl]methyl}pyridine-3-sulfonamide (reagent preparation 25) and [4-(6,6,7-trimethyl-5,6-dihydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.35 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.37 (s, 1H), 7.32 (d, 1H), 6.97 (d, 1H), 6.07 (s, 1H), 4.58 (s, 2H), 4.23 (m, 2H), 3.84 (m, 2H), 2.86 to 2.78 (m, 3H), 2.72 (m, 2H), 2.63 (s, 2H), 2.46 (m, 1H), 2.40 (s, 3H), 2.34 (m, 1H), 1.93 (m, 1H), 1.83 (s, 3H), 1.46 (m, 1H), 0.99 (s, 6H); MS (EI) for C31H39N7O3S: 590 (MH+).
Reaction SMILES: Cl.Cl.C[O:4][C:5](=[O:53])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH:47]5[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:54][C:55]1[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=1)[C:58](Cl)=[O:59]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH:47]1([CH2:46][O:45][C:42]2[CH:41]=[CH:40][C:39]([C@H:37]3[CH2:36][O:35][C:31]4=[CH:32][C:33]5[CH2:34][C@@H:25]([C:23]([NH:22][C@@H:6]([CH2:7][C:8]6[CH:9]=[CH:10][C:11]([C:14]7[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=7[CH3:21])=[CH:12][CH:13]=6)[C:5]([OH:53])=[O:4])=[O:24])[N:26]([C:58](=[O:59])[C:57]6[CH:61]=[CH:62][CH:63]=[C:55]([CH3:54])[CH:56]=6)[CH2:27][C:28]=5[CH:29]=[C:30]4[O:38]3)=[CH:44][CH:43]=2)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(-c3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCC3CCCCC3)cc2)O4)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (20 mg) was dissolved in 1:1 EtOAc and saturated aqueous NaHCO3 and 3-methylbenzoyl chloride (3 eq) added. After stirring at room temperature 1 hour, the layers were separated and the organic layer was dried over Na2SO4 and evaporated. The residue was purified by over silica (hexanes to 8:2 hexanes-EtOAc to 6:4 hexanes-EtOAc to 6:4 hexanes-EtOAc+2% MeOH to DCM+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (15 mg). LCMS (m/z): 795.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[C:26]([N:28]1[CH2:34][CH2:33][CH2:32][CH:31]([CH2:35][CH2:36]OS(C)(=O)=O)[CH2:30][CH2:29]1)=[O:27])(C)(C)C.C(CN)O.C1CCCCC1.[C:52]([O:55][CH2:56]C)(=[O:54])C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][OH:20])[C:26]([NH:28][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][C:52]([O:55][CH3:56])=[O:54])=[CH:35][CH:36]=2)=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC(CCNCCO)CC1
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: NCCO
Product: COC(=O)CCc1ccc(NC(=O)N(CCO)CCC2CCCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
The N-[2-(1-tert.butyloxycarbonyl-1-aza-4-cycloheptyl)-ethyl]-ethanolamine used as amine component is obtained by reacting 1-tert.butyloxycarbonyl-4-[2-(methane-sulfonyloxy)-ethyl]-1-azacycloheptane with ethanolamine. Rf value: 0.27 (Silica gel; cyclohexane/ethyl acetate=3:7)
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11](=O)[C:10]2=O)[CH3:3].[NH2:22][N:23]1[C:27]([NH2:28])=[N:26][N:25]=[C:24]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>C(O)CO.O>[ClH:1].[CH2:2]([N:4]([CH2:20][CH3:21])[CH2:5][CH2:6][C:7]1[C:8]([CH3:19])=[C:9]2[C:13](=[C:14]([CH3:16])[CH:15]=1)[NH:12][C:11]1[C:10]2=[N:22][N:23]2[C:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[N:25][N:26]=[C:27]2[N:28]=1)[CH3:3]
Reactant: CCN(CC)CCc1cc(C)c2c(c1C)C(=O)C(=O)N2
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Agent: Cl
Solvent: O
Solvent: OCCO
Product: CCN(CC)CCc1cc(C)c2[nH]c3nc4nnc(Cc5ccc(O)cc5)n4nc3c2c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.60 mmol of 5-(2-Diethylamino-ethyl)-4,7-dimethyl-1H-indole-2,3-dione hydrochloride (186.5 mg) and 0.70 mmol of 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol (144 mg) in 1.5 mL of ethylene glycol was stirred at 125° C. for 1 day. The mixture was cooled to room temperature, diluted with water (5 mL), stirred for 10 min. Allowed to crystallize in a refrigerator (+5° C.) overnight. The precipitated product was collected by filtration, washed with water (3×1 mL) and dried on high vacuum.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=S)[CH2:8][O:7][C:6]=2[N:12]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10]/[C:9](=[N:20]/[NH2:21])/[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: NN
Reactant: S=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Solvent: O
Solvent: C1CCOC1
Product: N/N=C1\COc2nc(Br)c(-c3ccccc3)cc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
In a 15 ml vial was 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazine-2(3H)-thione (100 mg, 0.311 mmol) and hydrazine monohydrate (0.049 ml, 1.557 mmol) in tetrahydrofuran (5 ml) to give a brown solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was slurred in diethyl ether. The supernatant solvent was removed and the brown solid vas dried until constant weigh to afford the title compound (90 mg, 90%). It was used for the next step without further purification. LCMS (Method D): RT 0.770 min, M+1=321.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][CH3:21]>C(O)C>[CH3:13][O:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][O:20][CH3:21])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COCCNCCOC
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COCCN(CCOC)c1nc(OC)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 90.6 %

Procedure:
4 g (0.0212 mol) of the product 2-chloro-3-nitro-6-methoxypyridine, 50 ml of ethanol and 6.32 ml (0.0424 mol) of bis(2-methoxyethyl)amine are placed in a fully equipped round-bottomed flask. The mixture is refluxed for 2 hours with stirring and is then poured onto an ice/water mixture with stirring. The precipitate formed is filtered off by suction and dried under vacuum to constant weight. 5.47 g of yellow powder are obtained, ie a yield of 90.6%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH:36]([CH3:38])[CH3:37])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Nc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At RT, 60 mg (0.11 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.011 ml (0.13 mmol) of isopropylamine were stirred in 1.5 ml of THF for 60 min. Another 11 μl (0.13 mmol) of isopropylamine were then added, and the mixture was stirred at RT for another 60 min. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 35 mg (56% of theory) of the desired target compound.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:38])[N:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]([CH3:27])[CH3:26])[CH:20]=[C:19]([Cl:39])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.ClCCl.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:39][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:25]([CH3:26])[CH3:27])=[O:38]
Reactant: CC(C)N(CCCNC(=O)C(C)(C)C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCCNC(=O)C(C)(C)C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [2-(3-chloro-5-{[3-(2,2-dimethyl-propionylamino)-propyl]-isopropyl-carbamoyl}-phenoxy)-ethyl]-pyridine-4-yl-carbamic acid tert-butyl ester in dichloromethane (1 ml) was treated with dichloromethane:trifluoroacetic acid (1:1 v/v) (1 ml), stirred for 3 h at room temperature and concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.039 g) as an oil.