Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-piperidone ethylene ketal (1.43 g, 10 mimol) and triethylamine (10 mmol, 1.4 ml) was added dropwise a solution of 4-methylbenzoyl chloride (1.55 g, 10 mmol) in ethyl acetate (20 ml) and the mixture stirred for 2 h. The mixture was washed twice with water followed by brine, dried over sodium sulphate and evaporated to give an off-white solid, m.p. 59°-61° C.
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[Br-:11].C(OC([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P+:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O)(C)(C)C.[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46].C(Cl)Cl>>[Br-:11].[NH3+:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][P+:26]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Br-:11].[C:45]([OH:51])([C:47]([F:50])([F:49])[F:48])=[O:46]
Reactant: CC(C)(C)OC(=O)NCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [Br-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [NH3+]CCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of TFA/CH2Cl2 (1:1, 50 ml) containing triisoproylsilane (0.2 ml) was added to (6-((tert-butoxycarbonyl)amino)hexyl)triphenylphosphonium bromide (8.0 g). The mixture was stirred for 2 hours. After removal of the solvent, the compound was dried over a vacuum and directly used in next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([NH:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[C:25](OC=O)(=[O:27])C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]([C@@H:15]([N:17]([CH:25]=[O:27])[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH3:16])[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(=O)OC=O
Reactant: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Solvent: c1ccncc1
Product: C[C@@H]([C@@H](CCCc1ccc(Cl)cc1)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution of (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid (380 mg, 1.07 mmol) in pyridine (4 mL) at 0° C. is added formic acetic anhydride (0.9 mL). The resulting solution is allowed to warm to 25° C., stirred for 3 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in ethyl acetate (30 mL) and washed sequentially with 1 M hydrochloric acid (20 mL) and saturated aqueous sodium chloride solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)butanoic acid as an oil (385 mg, 94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[O:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][O:9][CH2:10][CH2:11]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(N2CCCOCC2)nc1
Yield: 92.7 %

Procedure:
The solution of 5-bromo-2-chloropyridine (1.5 g, 7.8 mmol), 1,4-oxazepane (1.29 g, 9.36 mmol) and K2CO3 in 15 mL of NMP was stirred at 120° C. overnight. The mixture was added to 150 mL of water, washed with EA, dried over Na2SO4, and the volatiles were removed in vacuo to give 1.86 g of 4-(5-bromopyridin-2-yl)-1,4-oxazepane. MS(m/z)=259 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10](O)=[C:9](C(C)(C)C)[CH:8]=[C:7](C)[CH:6]=1)(C)(C)[CH3:2]>C(O)(C)C>[CH2:2]=[CH:1][CH:5]=[CH2:6].[CH2:2]=[CH:1][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(C)O
Product: C=CC=C
Product: C=Cc1ccccc1
Reaction time: 24 h

Procedure:
After 24 hours, the reaction was stopped by adding a stoichiometric quantity of 2,6-ditert-butyl-p-cresol and 0.5 phr added as an anti-oxidising agent. Butadiene-styrene copolymers were obtained by precipitation in isopropyl alcohol, and the structural and composition parameters thereof are given in Table III. Copolymerisation was practically random, as is deduced from the fact that no residue through degradative oxidation of the samples with hydroperoxide was observed during the analysis.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][CH2:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=O)=[N:8][C:4]=2[CH:3]=1.BrBr.[CH:26]([NH2:28])=[S:27].C(N)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:20][CH3:21])[C:7]([CH2:9][C:10]3[S:27][CH:26]=[N:28][C:11]=3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCn1c(CCC(=O)c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: NC=S
Agent: BrBr
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Solvent: NC=O
Product: CCn1c(Cc2scnc2-c2cccc(F)c2)nc2cc(Br)ccc21

Procedure:
A mixture of 3-(5-bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.2 g, 0.53 mmol) and bromine (0.1 g, 0.62 mmol) is refluxed in 1,4-dioxane for 2 hours. Thioformamide (freshly made from formamide and P2S5 in 1,4-dioxane) (1.3 mmol) are added to the solution. The mixture is refluxed overnight. The solvent is removed and NaHCO3 (aq.) (15 mL) and DCM (40 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×30 mL). The combined organic layers are dried and solvent removed. The crude is purified by PTLC (5% methanol in DCM) to give 5-bromo-1-ethyl-2-[4-(3-fluoro-phenyl)-thiazol-5-ylmethyl]-1H-benzoimidazole. 1H NMR (CDCl3) δ 8.78 (s, 1H), 7.91 (s, 1H), 7.38-7.48 (m, 4H), 7.11-7.19 (m, 2H), 4.59 (s, 2H), 3.90 (q, 2H), 1.12 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][S:19]([CH2:18][CH2:17][CH2:16][Cl:15])(=[O:21])=[O:20]
Reactant: COC(CN)OC
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(CNS(=O)(=O)CCCCl)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of aminoacetaldehyde dimethyl acetal (2.22 mL, 20.4 mmol) and triethylamine (3.54 mL, 25.4 mmol) in dichloromethane (60 mL) was added 3-chloropropanesulfonyl chloride (2.06 mL, 16.9 mmol) in dichloromethane (40 mL) dropwise. The reaction mixture was warmed to room temperature and stirred one hour. The reaction mixture was quenched with water. The organic phase was washed with water and brine, then dried over sodium sulfate. Filtration and concentration, followed by trituration with ether provided N-[2,2-bis(methyloxy)ethyl]-3-chloro-1-propanesulfonamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.56 (s, 1 H), 4.42 (t, J=5.0 Hz, 1 H), 3.68 (t, J=6.1 Hz, 2 H), 3.42 (s, 6 H), 3.25-3.21 (m, 4 H), 2.28 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[F:13][C:14]([F:28])([F:27])[C:15]1[N:20]=[CH:19][C:18]([C:21]2([CH:25]=[O:26])[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.CCOC(C)=O>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:25]([C:21]1([C:18]2[CH:19]=[N:20][C:15]([C:14]([F:28])([F:13])[F:27])=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22]1)[OH:26]
Reactant: O=CC1(c2ccc(C(F)(F)F)nc2)CCC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1ccccn1)C1(c2ccc(C(F)(F)F)nc2)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 4.6 %

Procedure:
To solution of 2-bromopyridine (506 mg, 3.2 mmol) in THF (10 mL) was added dropwise n-BuLi (2.4 mL, 3.84 mmol, 1.6 M) at −78° C. under nitrogen. After stirring for 30 minutes at −78° C., a solution of Example 85F (733 mg, 3.2 mmol) was added and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was allowed to warm up to room temperature, quenched with water (20 mL), extracted with dichloromethane (30 mL×2). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-TLC eluting with petroleum ether:EtOAc=2:1 to provide the title compound (45 mg, 4.6% yield) as a white solid. LC-MS: m/z 309.1 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J=4.4 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 7.57-7.61 (m, 1H), 7.46-7.49 (d, J=8.0 Hz, 1H), 7.34-7.39 (m, 1H), 7.14-7.17 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 5.05 (s, 1H), 4.51 (brs, 1H), 2.70-2.814 (m, 2H), 2.34-2.43 (m, 2H), 1.90-2.16 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C[O:22][C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:25]2[N:26]=[CH:27][NH:28][C:24]=12.C(O)CO>CO>[CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[C:8]([N:28]2[C:24]5[C:23](=[O:22])[NH:31][C:30]([NH2:32])=[N:29][C:25]=5[N:26]=[CH:27]2)[C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)cc1ccc3cccc4ccc2c1c34
Reactant: COc1nc(N)nc2nc[nH]c12
Agent: *CC(*)C
Solvent: CO
Solvent: OCCO
Product: Nc1nc2ncn(-c3c4ccccc4c4ccc5cccc6ccc3c4c65)c2c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
While the blocking reaction is progressing, NAb (selective for BP-6-N7Gua) and BP-6-N7Gua or benzo[a]pyrene (BP) or methylguanine (Me-N7Gua) or other structures related to BP-6-N7Gua are combined in separate Eppendorf tubes (1.5 mL polypropylene tubes). MAb is diluted 1:500 to 1:5000 in TBS buffer (0.05M Tris, 0.20M NaCl, pH 7.5) containing 10% (v/v) ethylene glycol as a protein stabilizer, then 500 uL is dispensed to each Eppendorf tube seated in a thermal mixing block set at 45 degrees C. These samples are heated for 10 minutes with vortexing. BP-6-N7Gua or BP or Me-N7Gua or other structures related to BP-6-N7Gua are diluted in methanol (MtOH), then added with vortexing in 10 uL volumes to duplicate samples of heated MAb solution. MtOH, alone, is added as a control to selected Eppendorfs. The reaction mixtures are heated with vortexing for an additional 20 minutes, then the reaction mixtures are cooled by addition of 100 uL of TBS buffer with 10% ethylene glycol. The reaction mixtures are incubated an additional 45 minutes at 37 degrees C.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Product: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Yield: 97 %

Procedure:
A mixture of 4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine (1.2 g, 4.68 mmol) and POCl3 (25 ml) was heated at reflux for 1 hour. The mixture was cooled and evaporated to dryness. The residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness to give 1.24 g (97%) of golden crystals, mp 82–84° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2C=O.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].[H-].[CH2:16]([Al+]CC(C)C)C(C)C>CCCCCC>[CH:1]12[CH2:7][CH:4]([CH:3]=[CH:2]1)[CH2:5][CH2:6]2.[CH3:16][CH:11]([CH2:12][CH3:13])[CH2:10][NH2:14]
Reactant: O=CC1CC2C=CC1C2
Reactant: CC(C)C[Al+]CC(C)C
Reactant: CCCCN
Agent: [H-]
Solvent: CCCCCC
Product: C1=CC2CCC1C2
Product: CCC(C)CN
Temperature: -18 °C
Reaction time: 0.08 h

Procedure:
79.0 g of 5-norbornene-2-carboxaldehyde (NBCXA), (77.6 ml, 0.647 mole) were dissolved in 500 ml of hexane. 47.3 g of n-butylamine (64 ml, 0.647 mole) was slowly added at 25° C. The solution was stirred for five minutes and cooled to -18° C. for several hours. The liquid hexane layer was decanted under nitrogen to remove the precipitated water which had frozen to ice and adhered to the sides of the reaction vessel. The clean hexane solution was removed under nitrogen to a separate reactor and dried with 50 gms of dried 4A molecular sieve. After thirty minutes, the hexane layer containing the n-butyl imine of NBCXA was separated from the molecular sieves and to it was added at -10° C. 80.3 gm (0.647 mole) of diisobutylaluminum hydride as a 15% solution in hexane under nitrogen. The solution was stirred under nitrogen for one hour to yield the MNCM of 5-norbornene-2-methyl-(N-n-butyl) amine. The reactions are summarized below: ##STR22##
Reaction SMILES: [CH3:1][C:2]1NC(C)=C(C(OC(C)C)=O)[CH:4]([C:15]2[C:20]3=[N:21][O:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[C:3]=1[C:24]([O:26][CH3:27])=[O:25].N1[O:29]N=C2C(C=O)=CC=CC=12.C(OC)(=O)CC(C)=O.N1CCCCC1>C(OC(C)C)(C)C.C(O)(=O)C>[CH3:27][O:26][C:24](=[O:25])[C:3]([C:2](=[O:29])[CH3:1])=[CH:4][C:15]1[C:20]2=[N:21][O:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12
Reactant: O=Cc1cccc2nonc12
Agent: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CC(C)OC(C)C
Product: COC(=O)C(=Cc1cccc2nonc12)C(C)=O

Procedure:
To achieve the afore-mentioned objects, the present invention provides for a process for the manufacture of the Isradipine which, involves two steps. In the first step 2,1,3-benzoxadiazole-4-carboxaldehyde is reacted with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. The product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is isolated and purified to get substantially high purity product with less than 0.3% 2,1,3-benzoxadiazole-4-carboxaldehyde content present in the purified product. In the second step the purified intermediate 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is reacted with isopropyl-β-aminocrotonate in ethanol at 25 to 35° C. The crude Isradipine is crystallised from ethanol to get pure Isradipine having substantially higher purity and containing lower amount of the symmetrical ester isomers (III) and (IV).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([N:18](S(C)(=O)=O)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:27][C:28](=[O:36])[C:29]([O:32]C(=O)C)([CH3:31])[CH3:30].Cl.C(Cl)Cl>O.CO>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:27][C:28](=[O:36])[C:29]([OH:32])([CH3:31])[CH3:30]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(O)C(=O)Nc1ccc(Sc2ccc(NS(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of lithium hydroxide monohydrate (0.177 g) in water (1.8 ml) was added to a stirred solution of N-{2-chloro-4-[4-(N,N-dimesylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methylpropanamide (Method 26) (0.45 g) in methanol (3.5 ml) and the mixture was stirred at ambient temperature for 4 hours. Water (3 ml) was added and the solution was acidified to pH 2-3 with 1M hydrochloric acid. DCM (20 ml) was added and the organic layer was washed with water (20 ml) and brine, then dried. Volatile material was removed by evaporation and the residue was purified by flash chromatography eluting with 30-70% ethyl acetate/hexane to give the title compound (0.30 g) as a solid. Mp 138-140° C.; NMR (CDCl3): 1.5 (s, 6H), 3.0 (s, 3H), 7.1-7.4 (m, 7H), 8.4 (d, 1H), 9.3 (s, 1H); MS (ESP−): 413; EA: found: C, 48.9; H, 4.4; N, 6.5%; C17H19ClN2O4S2 requires C, 49.2; H, 4.6; N, 6.8%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC.[F-].[K+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[N:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1sc(-c2ncccn2)nc1C(F)(F)F
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester (303 mg), 2-tributylstannanyl-pyrimidine (553 mg) and dichlorobis(triphenylphosphine)-palladium (II) (70 mg) in dioxane (5 mL) is heated at 110° C. in a sealed tube overnight. After the reaction mixture is cooled, a potassium fluoride solution and EtOAc are added and the mixture is stirred for 1 h and filtered. The organic layer is separated and aqueous layer is extracted with EtOAc once. The combined extracts are concentrated and the residue is purified by chromatography (silica gel, 4:1 Hexane and EtOAc) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:31])([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:37]#[C:38]Br>CO.O>[NH2:37][C:38]1[O:30][C:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)([CH3:31])[CH2:2][N:1]=1
Reactant: N#CBr
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(O)CN)c2c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(C)CN=C(N)O3)c2c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
To a mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}-2-methylpropan-2-ol (200 mg, 0.45 mmol, prepared in analogy to Example 11-4) and potassium acetate (240 mg, 2.4 mmol) in methanol (8 mL) and water (2 mL) which was cooled to 0° C., a cooled solution of cyanogen bromide (52.3 mg, 0.5 mmol) in methanol (2 mL) was added. After being stirred at room temperature for 4 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 80 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 466, 1H NMR (400 MHz, CD3OD) δ ppm 7.95 (d, J=7.6 Hz, 1 H), 7.83 (d, J=7.2 Hz, 1 H), 7.60 (m, 2 H), 7.46-7.39 (m, 2 H), 7.29 (dd, J=1.6, 8.8 Hz, 1 H), 6.19 (s, 1 H), 5.18-5.09 (m, 2 H), 4.51 (brs, 2 H), 3.82 (d, J=11.2 Hz, 1 H), 3.65 (s, 2 H), 2.57 (m, 3 H), 2.41 (s, 3 H), 1.62 (s, 3 H).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)[CH3:2]
Reactant: CC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]acetamide (22 mg, 0.066 mmol) and ammonium acetate (51.1 mg, 0.663 mmol) in methanol (0.37 mL) and acetonitrile (0.38 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (8.33 mg, 0.133 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (17 mg, 77%). The residue was used directly in the next step. LCMS calculated for C17H22ClN4O(M+H)+: m/z=333.1; found: 333.1.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11](OCC)=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19]>CO.CCO>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11]([NH:19][CH3:18])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CCOC(=O)C[C@H]1COc2cc(F)ccc2N1
Solvent: CO
Solvent: CCO
Product: CNC(=O)C[C@H]1COc2cc(F)ccc2N1
Temperature: 20 °C
Yield: 99.2 %

Procedure:
Ethyl [(3S)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 10a, 50.0 g, 204.2 mmol) was dissolved in MeOH (150 mL) in a 500 mL jacketed vessel at 20° C. Methylamine (127 mL of a 33% w/w solution in EtOH, 96 g, 1.02 mol) was added in one portion and the mixture stirred at 20° C. over night. The solution was sampled and found not to have reached completion by HPLC analysis. The reaction was left stirring for a further 2 h then additional methylamine in EtOH (25.0 mL of a 33% w/w solution in EtOH; 18.9 g; 200.8 mmol) was added and the solution stirred over night at 20° C. The solution was evaporated in vacuo to an orange oil, then MeOH (300 mL) added and the mixture re-evaporated giving a beige solid, that was ground up using a mortar and pestle, then dried in a vacuum oven at 40° C. for 3 h to yield the title compound (46.3 g, 99.2% yield NMR assay 98.1% w/w, 99.7% e.p. by chiral HPLC %).
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH3:42])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: C[C@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(Cl)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (9.2 g) was suspended in dichloroethane (110 ml) and pyridine (3.15 ml), and a solution of (S)-2-(4-chlorobenzenesulfonylamino)propionyl chloride (8.9 g) in dichloroethane (25 ml) was added dropwise over 5 minutes with siring under ice-cooling. The mixture was sired at room temperature for 3 hours and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 15.7 g of methyl (±)-4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (27 ml) and isopropyl ether (108 ml) and the obtained crystals were recrystallized from ethyl acetate (15 ml) and isopropyl ether (30 ml) to give 5.2 g of methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(4-chlorobenzenesulfonylamino)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate as white crystals, melting point 126-128° C.