Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccc2ncccc2c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and 6-aminoquinoline (73.7 mg, 0.51 mmol). The title compound was obtained as a yellow solid (52 mg, 25% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.84 (1H, br), 9.02 (2H, m), 8.825 (1H, m), 8.81 (1H, m), 8.34 (1H, m), 8.32 (1H, m), 8.04 (1H, m), 7.97 (1H, m), 7.51 (1H, m). MS m/z: 475.18, 477.09 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[C:9](=[O:19])[N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.Br[C:28]1[CH:29]=[C:30]2NC(=O)N(C(OCCCC)=O)[C:31]2=[N:32][CH:33]=1.[C:45]1(C(O)C)[CH:50]=CC=[CH:47][CH:46]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:13]1([CH:11]([N:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:47]4[CH:46]=[CH:45][CH:50]=[C:31]5[C:30]=4[CH:29]=[CH:28][CH:33]=[N:32]5)[CH:3]=3)[NH:8][C:9]2=[O:19])[CH3:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCOC(=O)n1c(=O)[nH]c2cc(Br)cnc21
Reactant: CC(c1ccccc1)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(Br)cc21
Reactant: CC(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
tert-Butyl 6-bromo-2-oxo-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate. To a solution of tent-butyl 6-bromo-2-oxo-1H-imidazo[4,5-b]pyridine-3(2H)-carboxylate (See Example 166.C) (0.60 g, 1.97 mmol), 1-phenylethanol (0.289 g, 2.37 mmol) and triphenylphosphine (0.62 g, 2.37 mmol) in tetrahydrofuran (15 mL) was added diisopropyl azodicarboxylate (0.46 mL, 2.37 mmol). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (0.30 g, 36% yield). MS (ESI) m/z 418.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([NH:32][C@@H:30]([C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=3)[CH3:31])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (45 mg, 0.33 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (200 μL, 1.15 mmol). The reaction mixture was stirred at room temperature for 16 hours. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC (100×21.2 mm C18 column, CH3CN/water[10 mM Et2NH]) to afford a light color solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:40][C@H:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[C:47]1[N:48]=[C:49]([C:62]2[CH:63]=[N:64][C:65]([NH2:68])=[N:66][CH:67]=2)[C:50]2[CH2:55][CH2:54][N:53]([C@@:56]3([CH3:61])[CH2:60][CH2:59][NH:58][CH2:57]3)[C:51]=2[N:52]=1.O>CN(C=O)C>[NH2:68][C:65]1[N:66]=[CH:67][C:62]([C:49]2[C:50]3[CH2:55][CH2:54][N:53]([C@@:56]4([CH3:61])[CH2:60][CH2:59][N:58]([C:10](=[O:12])[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:14])[CH3:13])[CH2:57]4)[C:51]=3[N:52]=[C:47]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][C@@H:41]3[CH3:40])[N:48]=2)=[CH:63][N:64]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCNC1)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)C(C)(C)NC(=O)OC(C)(C)C)C1)CC2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 77.8 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (728 mg, 3.58 mmol) in anhydrous DMF (13.8 mL) at 0° C. was added HATU (1570 mg, 4.13 mmol) portionwise, and the mixture was stirred at 0° C. for 40 min. 5-{2-[(3S)-3-methylmorpholin-4-yl]-7-[(3S)-3-methylpyrrolidin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}pyrimidin-2-amine hydrochloride (1294 mg, 2.757 mmol) and TEA (1.92 ml, 13.8 mmol) were added and the reaction mixture was stirred at room temperature for 2 h. Water was added, the mixture was extracted with EtOAc (3 times), the combined organic layers were washed with brine, and dried over Na2SO4. The residue was purified via ISCO silica gel chromatography (40 g column) using a gradient of 0-100% EtOAc containing 10% MeOH/EtOAc to give the title compound (1247 mg, 78%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 2 H), 6.59 (br s, 3 H), 4.67-4.54 (m, 1 H), 4.23 (d, J=11.5 Hz, 1 H), 3.92 (d, J=14.2 Hz, 1 H), 3.83 (d, J=11.4 Hz, 1 H), 3.70-3.40 (m, 7 H), 3.22-3.05 (m, 6 H), 2.12-2.02 (m, 1 H), 1.37 (s, 9 H), 1.35 (s, 6 H), 1.31 (s, 3 H). m/z (APCI+) for C29H43N9O4 582.7 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:28]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-fluoro-2-methylbenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methyl-benzenesulfonamide as a colorless oil. MS: 513.0 ([M+NH4]+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][C:13](O)=O>>[CH3:12][C:13]1[NH:11][S:8](=[O:9])(=[O:10])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1ccccc1S(N)(=O)=O
Product: CC1=Nc2ccccc2S(=O)(=O)N1
Yield: 91 %

Procedure:
2-Aminobenzenesulfonamide (17.2 g; 100 mmol) was refluxed in AcOH for 5 days. The precipitate formed was isolated by filtration and washed with water to give 17.8 g (91%) of 3-methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide. 3-Methyl-1,2-dihydro-1,2,4-benzothiadiazine-1,1-dioxide was transformed by Method A (using dimethylamine as amine). M.p. 260–261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ccc(Cl)cc12
Product: Clc1ccc2nccc(Cl)c2c1

Procedure:
From 93.6 g of 6-chloro-4-hydoxyquinoline and 200 ml of phosphorus oxychloride reacted in a manner similar to that described in Example 2(b) there was obtained 63.6 g of the above named compound as white needles, mp 101°-104°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(#N)C.[CH:18]1(/[CH:21]=[CH:22]/[C:23]#[N:24])[CH2:20][CH2:19]1.N12CCCN=C1CCCCC2>>[CH:18]1([CH:21]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:22][C:23]#[N:24])[CH2:20][CH2:19]1
Reactant: N#C/C=C/C1CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.0 g, 0.0515 mol) in acetonitrile (129 mL, 2.46 mol) was added (E)-3-cyclopropylacrylonitrile (5.75 g, 0.0617 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.85 mL, 0.0258 mol). The resulting mixture was stirred at room temperature overnight, and evaporated to dryness. The mixture was purified on silica gel, eluting with 0 to 80% EtOAc in hexanes, to give the desired product as racemic mixture (10.8 g, 73.0%). LCMS (M+H) 288.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.ClCCl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-Fluoro-2-nitrophenol (3.14 g; 20 mmol) and potassium carbonate (2.76 g; 20 mmol) are place in a round bottom flask and are flushed with argon. Dry dimethylformamide (60 mL) is added followed by dimethylsulfate (3.8 mL; 40 mmol). The reaction is stirred for 2 days at room temperature. Dichloromethane (120 mL) and water (60 mL) are then added. The aqueous phase is extracted with dichloromethane (100 mL) and the combined organic layers are washed three times with aq. sat. sodium hydrogencarbonate (50 mL), twice with aq. 1N hydrochloric acid (50 mL) and with brine (50 mL). The organic layer is then dried over magnesium sulfate and is concentrated under reduced pressure. The desired product is isolated in the presence of dimethylformamide (4.39 g).
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]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.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)(Cl)Cl>[CH3:29][S:30]([O:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][O:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)O[C@H]1CC[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-[(Trityloxy)methyl]cyclohexanol (2.72 g, 0.00730 mol) was dissolved in chloroform (30.0 mL) and the mixture was cooled at 0° C. To this mixture was added TEA (1.4 mL, 0.010 mol) and methanesulfonyl chloride (0.68 mL, 0.0088 mol) and the resulting mixture was stirred at 0° C. for 2 hours The reaction was then extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and the concentrated in vacuo. 1H NMR (CDCl3):δ 7.43 (m, 6H), 7.20-7.31 (m, 9H), 4.57 (m, 1H), 3.00 (m, 3H), 2.90 (m, 2H), 2.16 (m, 2H), 1.93 (m, 2H), 1.09-1.60 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][N:15]2[C:23](=[O:24])C3C(=CC=CC=3)C2=O)=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[OH2:27].NN>CO>[CH3:1][O:2][C:3](=[O:26])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][NH:15][C:23]([O:24][C:4]([CH3:5])([CH3:13])[CH3:3])=[O:27])=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O
Reactant: COC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1C(=O)OC
Agent: NN
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The compound (909 mg) obtained in Example 7-2 was suspended in methanol (22 ml). Hydrazine monohydrate (0.13 ml) was dropped in this suspension and the whole was refluxed under heating for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and then the residue was subjected to extraction with chloroform. The organic layer was washed with water and then with a saturated saline solution, followed by drying with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was dissolved in DMF (15 ml) and added with triethylamine (0.54 ml) and di-t-butyldicarbonate (851 mg), followed by stirring at room temperature for 15 hours. After the solvent was distilled off, the residue was subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and then dried with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (779 mg) as a yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([CH3:11])=[S:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].O.[OH-].[Na+].C>O1CCOCC1>[CH3:11][C:9]1[S:10][C:5]2[CH:4]=[C:3]([O:12][CH3:13])[C:2]([CH3:1])=[CH:7][C:6]=2[N:8]=1
Reactant: COc1ccc(NC(C)=S)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2sc(C)nc2cc1C

Procedure:
120 g of 2-methyl-4-thioacetamino-anisole were dissolved in 80 ml of dioxane, 1 l. of water and 600 ml of 6N NaOH. After decantation of the liquid phase, the residue was redissolved with a mixture of 300 ml of water and 50 ml of 6N NaOH. The two solutions containing pure 2-methyl-4-thioacetamino-anisole were cleaned by addition of animal charcoal and stirring. A water solution of K3Fe(CN)6 was then added dropwise to the filtrate under stirring. After such addition, the solution, thus obtained, was stirred for 2 hours at room temperature. The reaction mixture was then poured into a Rutscher-Stendall liquid-liquid type extractor and the base was extracted with ether. The ethereal solution, thus obtained, after having been dried an anhydrous Na2So4, was concentrated and the residual oil was finally distilled under vacuum collecting the 158° C./3 mm. Hg fraction. Yield: 65 g. The product thus obtained was purified upon crystallization from ligroin in the presence of animal charcoal, thus obtaining a pure product melting at 89°-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]=[C:15]=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10].[CH3:17][NH:18][CH3:19].O.ClC1C=C(N(C)C(NC)=O)C=CC=1OS(CCl)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([N:18]([CH3:19])[CH3:17])=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10]
Reactant: CNC
Reactant: O=C=Nc1ccc(OS(=O)(=O)CCl)c(Cl)c1
Agent: CNC(=O)N(C)c1ccc(OS(=O)(=O)CCl)c(Cl)c1
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=O)Nc1ccc(OS(=O)(=O)CCl)c(Cl)c1

Procedure:
20 g of 3-chloro-4-chloromethylsulfonyloxy-phenylisocyanate (alternative name: chloromethanesulfonic acid 2-chloro-4-isocyanato-phenyl ester) were dissolved in 100 ml of acetone and 10 ml of a 45% strength dimethylamine solution were added, whilst cooling. After addition of water, N-(3-chloro-4-chloromethylsulfonyloxy-phenyl)-N,N'-dimethylurea precipitated: it was filtered off and dried.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]=2[N:19]=1.[NH2:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:26])=[CH:23][C:22]=1[O:37][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(O)(C)C>[F:14][C:9]1([F:15])[CH2:8][N:7]([CH:16]([CH3:18])[CH3:17])[C:6]2[N:19]=[C:2]([NH:20][C:21]3[CH:36]=[CH:35][C:24]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]4)=[O:26])=[CH:23][C:22]=3[O:37][CH3:38])[N:3]=[CH:4][C:5]=2[N:11]([CH3:12])[C:10]1=[O:13]
Reactant: CC(C)N1CC(F)(F)C(=O)N(C)c2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Yield: 30.6 %

Procedure:
A mixture of 0.07 g (0.24 mmole) of 2-chloro-7,7-difluoro-9-isopropyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-292b), 0.070 g (0.26 mmole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.069 g (0.36 mmole) of p-toluenesulfonic acid monohydrate and 4 mL of isopropanol was heated in a pressure tube at 140 degrees overnight. After cooling, dichloromethane and saturated sodium carbonate were added. The mixture was extracted with dichloromethane twice. The combined organic layers were washed three times with sodium carbonate, times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.038 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-293) as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:26][C:13]([C:10]2[CH2:9][C:8]3([CH2:7][CH2:6][CH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:17][CH2:16]3)[O:12][N:11]=2)=[O:15])=[CH:27][CH:28]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)C2=NOC3(CCC(C(C)(C)C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (220 mg, 0.91 mmol), 4-tert-butylaniline (137 mg, 0.91 mmol), 4-methylmorpholine (279 mg, 2.76 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (528 mg, 1.20 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, ether/hexane 2:1), the desired product 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid-(4-tert-butylphenyl)amide was obtained as a diastereomer mixture in a yield of 80 mg (24% of the theoretical amount).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[CH:3]1[NH:14]C(=O)OCC1C=CC=CC=1.Br.CC(O)=O>CCOCC>[NH2:14][CH:3]1[C:2]([CH3:1])([CH3:25])[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4]1=[O:13]
Reactant: CC1(C)Sc2ccccc2NC(=O)C1NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1(C)Sc2ccccc2NC(=O)C1N
Yield: 80.6 %

Procedure:
Benzyl 2,2-dimethyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepin-3-ylcarbamate (0.67 g, 1.88 mmol, Eq: 1.00, WO96/11940) and 33% HBr/HOAc (9 μl, 54.7 mmol, Eq: 29) were combined to give a yellow solution. After 75 min. the mixture was diluted with 100 mL Et2O. The resulting precipitate was collected by filtration, washed with Et2O and added to 100 mL of aq. NaHCO3. The mixture was extracted with EtOAc and DCM. The combined extracts were dried over Na2SO4, filtered and the filtrate concentrated to give the title compound as a white solid (0.3370 g, 81%) which was used without purification. MS m/z 379.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[NH2:7][C@@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10].[O-]S([O-])(=O)=O.[Mg+2].C[Si](C)(C)[C:25]#[N:26]>C(Cl)(Cl)Cl>[OH:10][CH2:9][C@@H:8]([NH:7][C@H:5]([C:2]1([CH3:1])[CH2:3][CH2:4]1)[C:25]#[N:26])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: N[C@H](CO)c1ccccc1
Reactant: CC1(C=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: CC1([C@H](C#N)N[C@H](CO)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.7 %

Procedure:
To a solution of 1-methyl-cyclopropanecarbaldehyde (1.85 g, 22.0 mmol) in CHCl3 (30 mL) was added (S)-2-amino-2-phenylethanol (2.74 g, 20.0 mmol) and MgSO4 (3 g). The cloudy reaction mixture was stirred at room temperature for 3 hr then filtered, rinsing with CHCl3 (10 mL). Cooled to 0° C. and slowly added trimethylsilanecarbonitrile (5.0 ml, 39.9 mmol). The orange reaction mixture was stirred at 0° C. for 1 hr then allowed to warm to room temperature overnight. The reaction was quenched with 1.0 M HCl and stirred vigorously for 5 min then neutralized with 10% aqueous NaOH and extracted with CH2Cl2. The combined organics were dried over MgSO4 and concentrated to a light orange oil. NMR analysis showed that some TMS-ether remained. The crude product was treated with 10 mL of 3.0 M aqueous HCl for 10 min at which time TLC verified that the silyl group was removed. Extracted with CH2Cl2 (2×), dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (10-30% EtOAc/hexanes) to isolate 1.0 g (22%) of (R)-2-((S)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrile as a colorless oil and a single diastereomer.
Reaction SMILES: [CH2:1]([C:5]1(C=O)[NH:9][CH:8]=[CH:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])[CH2:2][CH2:3][CH3:4].C[Li].[O:22]1CC[CH2:24][CH2:23]1>>[CH2:1]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:7]([CH:23]([OH:22])[CH3:24])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C=O)NC=CN1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: [Li]C
Product: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-carboxaldehyde (Example 1(iii)) (1.1 g, 3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argon and a solution of methyl lithium (3.64 ml of 1.2 M in diethyl ether, 4.57 mmol) was added dropwise. The mixture was stirred for 1.5 hours, quenched with ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The washed, dried, concentrated product was flashed chromatographed over silica gel with ethyl acetate to provide 1.07 g (92%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy)ethyl-1H-imidazole.