Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=CC=1C=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19](F)[C:16]=1[CH:17]=O.O.[NH2:30][NH2:31]>CS(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:16]=1[CH:17]=[N:30][NH:31]2
Reactant: O=Cc1c(F)ccc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: NN
Agent: O=Cc1ccccc1F
Solvent: CS(C)=O
Solvent: O
Product: Clc1cc(Br)cc(Oc2c(Cl)ccc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-(3-bromo-5-chlorophenoxy)-3-chloro-6-fluorobenzaldehyde fluorobenzaldehyde (4.5 kg; 12.36 moles; 1.0 eq.) in DMSO (18 L) was degassed, after which hydrazine monohydrate (6.192 kg; 123.7 moles; 10.0 eqs.) was added over 20 minutes at room temperature. The reaction solution was degassed again, stirred at room temperature for 15 minutes, heated to 73° C., and then aged for 16 hours. After the mixture was cooled to room temperature, isopropanol (15 L) and then water (40 L) were added, and the resulting mixture cooled to room temperature, filtered under pressure, and washed with isopropanol:water (1:2; 10 L), water (12 L), and heptane (12 L). The title product as a solid was obtained after drying at 30° C.-35° C. under vacuum for four days.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[Cl-].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][NH2+:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C.C(O)(=O)C.C([BH3-])#N>ClC(Cl)C>[O:13]=[C:6]1[N:7]2[C:12]([CH:11]=[CH:10][CH:9]=[CH:8]2)=[C:3]([CH2:1][N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([F:20])([F:34])[F:35])=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)[CH:4]=[C:5]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reactant: FC(F)(F)c1ccc(C2CC[NH2+]CC2)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CN2CCC(c3ccc(C(F)(F)F)cc3)CC2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
In a 2-5 mL Emrys™ process vial, the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (599 mg, 2.44 mmol) and the 4-[4-(trifluoromethyl)phenyl]piperidinium chloride (672 mg, 2.53 mmol) were diluted with 4.9 mL of dichloroethane, which was neutralized with the addition of triethylamine (0.41 mL, 2.93 mmol). To the stirring mixture was added glacial acetic acid (0.84 mL, 14.7 mmol) and resin-bound MP-cyanoborohydride (307 mg, 4.89 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 20 minutes. After filtration, the filtrate was washed with water (3×20). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography eluting with 30-80% EtOAc in hexanes to provide ethyl 4-oxo-1-({4-[4-(trifluoromethyl)phenyl]piperidin-1-yl}methyl)-4H-quinolizine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][O:9][CH2:10][O:11][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.CN(CCN(CCN(C)C)C)C.C([Li])CCC.[CH:31](N1CCOCC1)=[O:32].Cl>C1COCC1>[F:1][C:2]1[C:7]2[CH2:8][O:9][CH2:10][O:11][C:6]=2[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[CH:31]=[O:32]
Reactant: COc1ccc(F)c2c1OCOC2
Reactant: O=CN1CCOCC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCOC2
Temperature: -74 °C
Reaction time: 1 h

Procedure:
To a solution of the 1.086 g of 5-fluoro-8-methoxy-4H-benzo[1,3]dioxine and 1.28 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 10 ml of THF there was added dropwise 2.4 ml of n-butyllithium (2.55 M, hexane solution) at −74° C. The mixture was stirred at −74° C. for 1 hour, and then 0.7 ml of N-formyhnorpholine was added. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added thereto while cooling on ice, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (153 mg) as an oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].I[C:6]1[C:7]([CH:19]2[CH:24]3[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]3)[CH2:20]2)=[N:8][N:9](COCC[Si](C)(C)C)[CH:10]=1.CCO.CCO.C(N(CC)CC)C>CCO.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:4][C:6]1[C:7]([CH:19]2[CH:24]3[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]3)[CH2:20]2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCCO
Reactant: C[Si](C)(C)CCOCn1cc(I)c(C2CN3CCC2CC3)n1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCOc1c[nH]nc1C1CN2CCC1CC2

Procedure:
Compound 52B was prepared following the procedure as described for the synthesis of compound 52A (see Scheme 10) using propanol and 3-[4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-3-yl]-1-azabicyclo[2.2.2]octane (50). Work-up and flash chromatography (gradient EtOH to EtOH/triethylamine 300/1) followed by a second flash chromatography (EtOH/ethyl acetate/triethylamine 25/75/1) afforded compound 51B as an oil (14%). LCMS (method B): Rt: 7.15 min, ([M+H]+=366). Compound 51A was subsequently deprotected (TBAF/THF) and purified by flash chromatography (gradient EtOH to EtOH/triethylamine 97/3), followed by a preparative TLC purification (CH3CN/H2O) to afford the title compound 52B as an oil. (51%). LCMS (method A); Rt: 0.91 min, ([M+H]+=236). 1H-NMR (600 MHz, D6DMSO): δ 7.34 (s, 1H), 3.74 (t, J=7 Hz, 2H), 3.24-3.19 (m, 1H), 3.03-2.96 (m, 1H), 2.92-2.87 (m, 1H), 2.86-2.74 (m, 3H), 2.69-2.62 (m, 1H), 1.88-1.84 (m, 1H), 1.67-1.55 (m, 5H), 1.26-1.20 (m, 1H), 0.92 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](CC#N)=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br.[C:15]([OH:18])(=O)[CH3:16].C([O:21]CC)C.CC(C)=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]2[CH2:16][C:15](=[O:18])[NH:10][C:9](=[O:21])[CH2:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCOCC
Reactant: N#CCc1cccc(Cl)c1CC#N
Agent: Br
Solvent: CC(C)=O
Product: O=C1Cc2cccc(Cl)c2CC(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 32.94 g of 2,2′-(3-chloro-1,2-phenylene)diacetonitrile in 100 ml of acetic acid was added dropwise 100 ml of a 33% hydrogen bromide-acetic acid solution over 1.5 hours while keeping the inner temperature at 20° C. or lower. The reaction mixture was stirred at room temperature for 3 hours, and then to the reaction mixture were added diethylether and acetone. The resulting candy-like dark brown solid substance and the suspension were separated, the suspension was concentrated under reduced pressure, and the candy-like substance was pulverized in acetone to obtain a suspension. The concentrated residue and the acetone suspension were combined and concentrated under reduced pressure, and to the residue was added EtOAc, followed by stirring. The solid was collected by filtration. The resulting solid was suspended in 400 ml of water which had been heated to 80° C., and 31.2 g of sodium acetate was added thereto, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and then the solid was collected by filtration to obtain 22.506 g of 6-chloro-1H-3-benzazepine-2,4(3H,5H)-dione as a brown solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH3:21][NH:22][CH3:23].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>C1COCC1>[CH3:21][N:22]([CH3:23])[C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12](/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[CH:13][CH:14]=1
Reactant: CNC
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
A mixture of a solution of (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid obtained in Step 6 in THF (0.125 mol/L, 0.40 mL, 0.05 mmol), a solution of dimethylamine in THF (1 mol/L, 0.08 mL, 0.08 mmol), a solution of 1-hydroxybenzotriazole in THF (0.33 mol/L, 0.20 mL, 0.07 mmol) and polymer-bound 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1 mol/g, 0.07 g, 0.07 mmol) was shaken at room temperature overnight. The reaction mixture was filtered, the solvent was evaporated by blowing air to the filtrate, and the residue was added with THF (0.6 mL), polyvinylpyridine (0.03 g, 0.29 mmol) and 4-chloroformyl polystyrene (3.5 mol/g, 0.03 g, 0.11 mmol), followed by shaking at room temperature overnight. The reaction mixture was filtered, and the solvent was evaporated by blowing air to the filtrate. The residue was added with ethanol (0.5 mL) and ion-exchange resin [Bio-Rad AG (registered trademark) 1 X-8 OH form, 0.15 g], followed by shaking for 10 minutes. The mixture was filtered, the resin was washed with ethanol, and the adsorbate was eluted with a 4 mol/L solution of hydrogen chloride in ethyl acetate. The solvent was evaporated by blowing air to the eluate, the residue was purified by thin-layer chromatography (chloroform/methanol=9/1) to obtain Compound 1 (0.4 mg, 3%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[CH3:37][CH:38]([CH2:43][C:44]([CH3:47])([CH3:46])C)[CH2:39][C:40](Cl)=[O:41].N1C=CC=C[CH:49]=1>C(Cl)Cl>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([NH:34][C:40](=[O:41])[CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][CH:44]([CH3:46])[CH3:47])=[C:27]([CH:32]=1)[C:26]([NH:25][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1)[C:3]([OH:36])=[O:2])=[O:35].[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[NH:34][C:40](=[O:41])[CH2:39][C:38]([CH3:37])([CH3:49])[CH2:43][CH:44]([CH3:46])[CH3:47])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Reactant: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC(C)(C)CC(=O)Nc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Br)ccc1NC(=O)CC(C)(C)CC(C)C
Reaction time: 1 h

Procedure:
A solution of (2S)-(2-amino-5-bromo-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (54.5 mg, 0.10 mmol) from example 294 in 1 mL dry CH2Cl2 was treated with 3,5,5-trimethylhexanoyl chloride(1.2 eq., 23 microL, 0.12 mmol) and pyridine (1.5 eq., 12 microL, 0.15 mmol) in succession and stirred under an atmosphere of dry N2 for one hour, then concentrated in vacuo. The crude residue was purified by flash column chromatography (hexanes, EtOAc) to afford the desired amide, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester, in quantitative yield (68 mg, 100%). The methyl ester (20 mg, 29 micromol) was dissolved in 2.0 mL THF and 0.5 mL MeOH and saponified with 2N aqueous LiOH solution (0.25 mL), as described in general procedure C, to afford the title compound, (2S)-[5-Bromo-2-(3,3,5-trimethyl-hexanoylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (20 mg, 100%), as a white solid. LCMS 673 (M+1)+. 1H NMR (400 MHz, CDCl3) 10.74 [s, 1H], 8.51 [d, 1H], 7.51 [m, 3H], 7.43 [m, 2H], 7.27–7.30 [m, 2H], 7.16–7.26 [m, 5H], 6.98 [d, 2H], 6.88 [d, 2H], 6.59 [d, 1H], 5.03 [dd, 1H], 3.28 [dq, 2H], 2.36 [m, 1H], 2.14 [m, 1H], 1.11–1.25 [m, 3H], 1.00 [s, 3H], 0.92 [s, 3H], 0.91 [d, 6H].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]>>[F:13][C:14]1[CH:15]=[CH:16][C:17]2=[C:18]([CH:34]=1)[O:19][CH2:20][C:21]1[CH:31]=[C:30]([CH:32]([C:8]3[N:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]4=[N:10][C:9]=3[CH3:11])[OH:33])[CH:29]=[CH:28][C:22]=1/[C:23]/2=[C:24](/[CH3:27])\[C:25]#[N:26]
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Reactant: Cc1nc2c(Cl)cccn2c1I
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C)nc4c(Cl)cccn34)cc2COc2cc(F)ccc21
Yield: 91.7 %

Procedure:
[step 3] Using 8-chloro-2-methyl-3-iodoimidazo[1,2-a]pyridine (598 mg, 2.05 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (300 mg, 1.02 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[(8-chloro-2-methylimidazo[1,2-a]pyridin-3-yl)(hydroxy)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (430 mg, 91%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.CO.Cl[C:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>C[O-].[Na+].CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Reactant: SCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(C(=CC(=O)N2CCOCC2)SCc2ccc(Cl)cc2)cc1OC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3.17 g (20 mmol) of 4-chlorobenzylmercaptan are dissolved in 20 ml of methanol containing 3.60 g (20 mmol) of sodium methylate (30%), warmed to 50° C. and then evaporated. A solution of 4.68 g (15 mmol) of 3-chloro-3-(3,4-dimethoxyphenyl)-1-morpholin-4-ylprop-2-en-1-one in 20 ml of dimethylformamide is added. At the end of the exothermic reaction the solution is stirred at 100° C. for 1 hour and the solvent is evaporated. The residue is shaken with toluene/water, the organic phase is washed with water, dried and the reaction product is purified by flash column (150 g of silicagel) chromatography; elution with 1000 ml of toluene containing 10 and 20% of acetone. The fractions with TLC Rf-values 0.45 and 0.38 (toluene/acetone 7:3) are collected and evaporated.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].C(Cl)(=[O:10])C.O1C[CH2:15][CH2:14][CH2:13]1>>[C:1]([N:3]1[CH2:6][CH2:7][CH2:15][CH2:14][CH2:13][CH2:5][CH2:4]1)(=[O:10])[CH3:2]
Reactant: C1CCOC1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Product: CC(=O)N1CCCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of heptamethyleneimine (5.56 ml; 44 mmol) and triethylamine (6.13 ml; 44 mmol) in tetrahydrofuran (20 ml) under nitrogen at 0° C. was added dropwise a solution of acetyl chloride (3.13 ml; 44 retool) in tetrahydrofuran (20 ml). The reaction mixture was then warmed to room temperature and stirred for 1 hr. The resulting solid was filtered off and washed thoroughly with ether. The filtrate was evaporated in vacuo to give an orange oil. Distillation in vacuo gave the title compound (D9).
Reaction SMILES: [CH2:1]([O:3][CH:4]([S:46][CH2:47][CH3:48])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:45])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]=1[N+:42]([O-])=O)[CH3:2].CO.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([O:3][CH:4]([S:46][CH2:47][CH3:48])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:45])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:39]([O:40][CH3:41])=[CH:38][C:28]3[C:29](=[O:37])[N:30]4[CH2:36][CH2:35][CH2:34][C@H:31]4[CH2:32][NH:33][C:27]=3[CH:26]=2)=[CH:13][C:12]=1[NH2:42])[CH3:2]
Reactant: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCOC(SCC)[C@@H]1CCCN1C(=O)c1cc(OC)c(OCCCCOc2cc3c(cc2OC)C(=O)N2CCC[C@H]2CN3)cc1N

Procedure:
The (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-nitrobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal (702 mg, 1.0 mmol) of the formula III was dissolved in dichloromethane (5 mL), methanol (10 mL) and added SnCl2.2H2O (1.124 g, 5.0 mmol) was refluxed for 1.5 h. The reaction mixture was then carefully adjusted to pH 8 with saturated NaHCO3 solution and then extracted with ethylacetate (3×20 mL). The combined organic phase was dried over Na2SO4 and evaporated under vacuum to afford the crude (2S)-N-{4-[4-(7-Methoxy-(11aS)-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one-8-yloxy)butoxy]-5-methoxy-2-aminobenzoyl}pyrrolidine-2-carboxaldehyde diethyl thioacetal IV.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:66]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=1[S:75](Cl)(=[O:77])=[O:76])([O-:68])=[O:67]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][S:75]([C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=3[N+:66]([O-:68])=[O:67])(=[O:76])=[O:77])[CH:46]([O:51][CH2:52][CH3:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1OS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-ethoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 46) in dry methylene chloride (2 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The yellow solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:45])[CH3:44])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(C)(=O)=O)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]-acetamide via General Procedure A. Purification on silica and ether trituration gave 233. NMR (CDCl3): 2.25 (3H, s), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.35 (1H, s), 7.97 (1H, br. s), 8.28 (1H, d), 8.71 (1H, d), 9.30 (1H, s). MS (ESI+): MH+532.28 (100%)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[N:8]=[C:9]([NH:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:10][CH:11]=1)[C:4]([OH:6])=[O:5].[CH3:32][O:33][C:34]([CH3:36])=[CH2:35]>C(Cl)Cl>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:3](=[N:2][O:1][C:34]([CH3:36])([O:33][CH3:32])[CH3:35])[C:4]([OH:6])=[O:5])[N:8]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)OC
Reactant: O=C(O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: COC(C)(C)ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 12.9 g of the syn isomer of 2-hydroxyimino-2-(2-tritylamino-4-thiazolyl)-acetic acid, 120 ml of methylene chloride and 12 ml of 2-methoxy-propene was stirred at room temperature for 20 minutes and was evaporated to dryness. The residue was stirred with 60 ml of methylene chloride and 12 ml of 2-methoxy-propene for 30 minutes and the mixture was evaporated to dryness to obtain the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(1-methyl-1-methoxyethoxyimino)-acetic acid which was used as is for the next step.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[CH3:19]>[Fe](Cl)(Cl)Cl>[C:1]1([S:7]([C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([CH3:12])[CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Product: Cc1ccc(S(=O)(=O)c2ccccc2)cc1C
Temperature: 110 °C

Procedure:
110 g of o-xylene, 176 g of benzenesulphonyl chloride and 0.16 g of iron(III) chloride are brought together at room temperature and the mixture is heated at 110° C. in the course of 2 hours. When the evolution of HCl has ended, the mixture is heated to 140° C. and the product is discharged onto a metal sheet. On cooling, the melt solidifies to a colourless mass. Yield: 243 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Cl[CH2:16][O:17][CH2:18][CH3:19].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]([O:11][CH2:16][O:17][CH2:18][CH3:19])([CH3:10])[CH3:9]
Reactant: CC(=O)c1ccc(C(C)(C)O)c(Br)c1
Reactant: CCOCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOC(C)(C)c1ccc(C(C)=O)cc1Br
Temperature: 40 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A mixture of 1-(3-bromo-4-(2-hydroxypropan-2-yl)phenyl)ethanone (0.9 g, 3.51 mmol), (chloro-methoxy)ethane (660 mg, 7.02 mmol) and DIPEA (2.5 mL, 14.04 mmol) in DCM (20 mL) was stirred at 40° C. overnight under argon. Water (50 mL) was added and the mixture was extracted with DCM (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (10:1) to give 1-(3-bromo-4-(2-(ethoxymeth-oxy)propan-2-yl)phenyl)ethanone (990 mg; yield 90%) as a white solid.