Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH3:17][S:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1)(=[O:20])=[O:19].ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][S:18]([CH3:17])(=[O:19])=[O:20])=[CH:27][CH:26]=2)[CH2:7]1
Reactant: NCC1CN(Cc2cccc(F)c2)CCO1
Reactant: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CC(=O)NCC2CN(Cc3cccc(F)c3)CCO2)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture of Intermediate 29 (0.0134 g), {4-[(methylsulfonyl)amino]phenyl}acetic acid (0.0137 g, known compound WO 9929655 A1), 1-hydroxybenzotriazole (0.0097 g) and N,N-diisopropylethylamine (0.01 ml) in N,N-dimethylformamide (0.5 ml) was treated with a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.00138 g) in N,N-dimethylformamide (0.5 ml). The mixture was stirred at 20° C. for 24 h. The mixture was partitioned between dichloromethane (4 ml) and saturated aqueous sodium hydrogen carbonate (4 ml). The phases were separated and the organic phase applied to an ion exchange cartridge (2 g Isolute SCX, prewashed with methanol). The SCX cartridge was eluted with methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml) and the appropriate fractions were concentrated in vacuo to give the title compoundas a colourless (0.0174 g).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)[CH:15]=[CH2:14]
Reactant: Oc1cccc2cccnc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 3.0 g, 75 mmol) in DMF (100 mL) at 0° C. under argon, was added a solution of 8-hydroxyquinoline (9.2 g, 64 mmol) in DMF (20 mL) dropwise. The mixture was allowed to stir for 0.5 h, then allyl bromide (6.6 mL, 77 mmol) was added dropwise. The mixture was stirred at room temperature for 20 h, then was poured into ice/water (400 mL) and extracted with ether (3×300 mL). Combined organic extracts were washed with water (500 mL) and evaporated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate in hexane 25%-75% gradient) to give 8-allyloxyquinoline (8.5 g, 72%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[C:5]2=[CH:4][CH:3]=1.[CH3:30][Mg]I>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=CCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: -20 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
In a 100 mL dry flask, 4-{5-chloro-2-[(1-cyclopropyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]-1H-imidazo[4,5-b]pyridin-1-yl}butanal 67-1 (1.5 g, 3.6 mmol) was dissolved in dry THF (50 mL) and cooled until −20° C. under N2 atmosphere. An excess methylmagnesium iodide (3M in THF) (1.8 mL, 5.5 mmol, 1.5 eq.) was then gently added dropwise to the cooled solution via syringe. The solution was warmed up until ambient temperature and stirred for 4 hours. The solution was diluted with 30 mL NaHCO3 solution and extracted with EtOAC (30 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude was purified on RP SunFire Prep column (C18 OBD-10 μm, 30×150 mm), using a 0.25% NH4HCO3 solution in water-MeOH solution to give 350 mg (22%) of 3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (67) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.05 (m, 2H) 1.13-1.22 (m, 5H) 1.43-1.57 (m, 2H) 1.77-1.91 (m, 2H) 2.11 (br. s, 1H) 2.89-2.98 (m, 1H) 3.81-3.90 (m, 1H) 4.32-4.50 (m, 2H) 5.40 (s, 2H) 7.13 (dd, J=5.27, 0.75 Hz, 1H) 7.23 (d, J=8.53 Hz, 1H) 7.65 (d, J=8.28 Hz, 1H) 8.34 (d, J=5.27 Hz, 1H) 8.75 (s, 1H); LCMS m/z=427 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:16]#[N:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([N+:18]([O-])=O)[CH:5]=1.ClCCl>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([NH2:17])[NH:18]2)=[CH:8][CH:9]=1)=[O:21]
Reactant: CCOC(=O)C(C#N)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(N)[nH]c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Yield: 43.3 %

Procedure:
Zinc powder (4.9 g) was added portion-wise at 80° C. to a solution of 4-(cyano-ethoxycarbonyl-methyl)-3-nitro-benzoic acid methyl ester (4.40 g, 15 mmol) in acetic acid. The mixture was then heated for 3 hours at 95° C. and 3 hours at 100° C. before being allowed to cool to room temperature at which point the reaction mixture was filtered and the insoluble matter rinsed with acetic acid. The filtrate was concentrated to give a brown oil which was subjected to flash silica chromatography using ethyl acetate as eluent. The partially purified oil was taken up into dichloromethane and the product precipitated using hexane to give the title compound as a pale brown solid (1.71 g, 6.5 mmol). LC-MS (1) Rt 1.88 min; m/z 263.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ncc(Br)c[nH]1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cnc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromopyrimidin-2(1H)-one (3 g), methyliodide (1.1 mL) and K2CO3 (2.4 g) in N,N-dimethylformamide (60 mL) is stirred for 5 hours at room temperature. The mixture is filtered and the mother liquor is concentrated. The residue is partitioned between water and dichloromethane. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound. Yield: 385 mg; LC (method 9): tR=0.25 min; Mass spectrum (ESI+): m/z=189 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[C:42]5[CH2:46][CH2:47][CH3:48])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][N:41]5[CH:45]=[CH:44][N:43]=[C:42]5[CH2:46][CH2:47][CH3:48])=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCn4ccnc4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCn4ccnc4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(2-propylimidazol-1-yl)ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.78 g) was dissolved in methylene chloride (23.4 ml), and a solution of metachloroperbenzoic acid (0.34 g) in methylene chloride (15.6 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(2-propylimidazol-1-yl)ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 305) (345 mg).
Reaction SMILES: Br[C:2]12[CH2:11][C:6]3([CH3:12])[CH2:7][CH:8]([CH2:10][C:4]([CH3:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Na]>C1(C)C=CC=C(C)C=1>[CH3:8][C:2]12[CH2:9][CH:8]3[CH2:7][C:6]([CH3:12])([CH2:5][C:4]([C:13]45[CH2:13][C:4]6([CH3:10])[CH2:3][CH:2]([CH2:11][C:6]([CH3:12])([CH2:5]6)[CH2:7]4)[CH2:9]5)([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: [Na]
Solvent: Cc1cccc(C)c1
Product: CC12CC3CC(C)(C1)CC(C14CC5CC(C)(CC(C)(C5)C1)C4)(C3)C2

Procedure:
A coupling reaction of 1-bromo-3,5-dimethyladamantane (Compound A100, product of Aldrich) is caused in m-xylene by the addition of metal sodium, whereby 3,3′,5,5′-tetramethyl-1,1′-biadamantane (Compound A101) is obtained. Compound A101 is then brominated with bromine into a dibromotetramethylbiadamantane derivative (Compound A102). Compound (A102) is reacted with vinyl bromide into Compound A103. The compound A103 is reacted with t-butoxypotassium to obtain 5,5′,7,7′-tetramethyl-3,3′-diethynyl-1,1′-biadamantane (Compound A 104). Moreover, in accordance with the synthesis process shown in <Synthesis of Exemplified compound D-102>, a target Exemplified compound (D-134) (5,5′,7,7′-tetramethyl-3,3′-divinyl-1,1′-biadamantane) is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:24][C:23](=O)[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:36])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]=[C:23]([Cl:36])[C:22]3[C:17](=[CH:18][C:19]([O:31][CH3:32])=[C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:21]=3)[N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc2c(=O)[nH]c(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1cc2c(Cl)nc(-c3cccc(OCc4ccccc4)c3)nc2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
To a suspension of 2-(3-(benzyloxy)phenyl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one (3.28 g, 7.58 mmol) in CH2Cl2 (100 mL) was added oxalyl chloride (2.20 mL, 24.8 mmol) and 2 drops of DMF. The mixture was stirred at RT for 6 h. An additional aliquot of oxalyl chloride (1.20 mL, 13.5 mmol) was added. Stirring was continued at RT overnight, upon which the mixture was concentrated in vacuo, taken up in CHCl3 (100 mL) and washed with sat. NaHCO3 (3×50 mL), water (2×50 mL) and brine (1×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 2-(3-(benzyloxy)phenyl)-4-chloro-7-methoxy-6-(2-methoxyethoxy)quinazoline (1.52 g, 3.37 mmol, 45%). MS 451 (M+1 Cl isotope pattern). HPLC retention time 10.84 mins. (10-95-13 method).
Reaction SMILES: Br[C:2]1[N:3]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=1.C([C:27]([O:29][CH2:30][CH3:31])=[O:28])#N>>[CH3:22][Si:21]([CH3:24])([CH3:23])[CH2:20][CH2:19][O:18][CH2:17][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:6]=[C:2]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1Br
Reactant: CCOC(=O)C#N
Product: CCOC(=O)c1nc(C(=O)OCc2ccccc2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 52(d) starting from benzyl 2-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.609 mmol, 250 mg) and ethyl cyanoformate (0.91 mmol, 90 mg). Yield 97 mg. 1H-NMR (400 MHz; CDCl3): δ −0.08 (s, 9H), 0.91 (t, 2H), 1.42 (t, 3H), 3.57 (t, 2H), 4.43 (q, 2H), 5.38 (s, 2H), 5.78 (s, 2H), 7.30-7.39 (m, 3H), 7.43-7.46 (m, 2H), 7.90 (s, 1H). LC-MS: [M+1]=405.13.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=[C:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:19]=3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=O)[O:39]C2C=CC=CC=2)[CH:32]=1.C(N(CC)CC)C>CS(C)=O>[CH:8]1([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:24]=[C:25]3[CH2:30][CH2:29][N:28]([C:38]([NH:37][C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[O:39])[CH2:27][CH2:26]3)=[N:15][CH:16]=2)[CH2:10][CH2:9]1
Reactant: C(=C1CCNCC1)c1cccc(Oc2ccc(C3CC3)cn2)c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(C4CC4)cn3)c2)CC1
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of 5-cyclopropyl-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine trifluoroacetate (125 mg, 0.408 mmol) in DMSO (5 mL) was added phenyl pyridin-3-ylcarbamate (87.4 mg, 0.408 mmol) followed by triethylamine (0.12 mL, 0.82 mmol). The reaction was heated to 60° C. overnight and then allowed to cool to RT. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried and concentrated. Purification by silica gel column chromatography (0-5% MeOH/CH2Cl2) afforded the title compound as a white foam (101 mg, 58% yield). MS (APCI 10V) AP+2 427.07; 1H NMR (400 MHz, CDCl3) δ ppm 0.61-0.66 (m, 2H) 0.93-0.99 (m, 2H) 1.55 (s, 1H) 1.81-1.89 (m, 1H) 2.45 (t, 2H) 2.58 (t, 2H) 3.50 (t, 2H) 3.60 (t, 2H) 6.38 (s, 1H) 6.44 (s, 1H) 6.80 (d, 1H) 6.94 (br. s., 1H) 6.96-7.01 (m, 2H) 7.20-7.23 (m, 1H) 7.29-7.35 (m, 2H) 7.99-8.01 (m, 1H) 8.26 (d, 1H) 8.42 (d, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.O>C1COCC1>[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40][N:2]([CH3:1])[C:3](=[O:24])[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:8][C:7]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[N:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1cnc(N2CCN(C)CC2)cc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(N2CCN(C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 2.5 g (7.7 mmol) N-methyl-6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide in 51 ml THF at 4° C. was added dropwise over 30 min 10.2 ml (10.2 mmol) potassium bis(trimethylsilyl) amide (1M in THF). The reaction mixture was stirred for 30 min and subsequently treated at 4° C. dropwise over 30 min with 1.46 ml (7.7 mmol) 3,5-bis-trifluoromethyl-benzylbromide. The reaction mixture was stirred for 1.5 h at 4° C., treated with 31 ml water and extracted. The aqueous phase was separated and adjusted to pH 12 with 2N NaOH and subsequently extracted with 30 ml ethyl acetate. The aqueous phase was separated, the combined organic phases were dried over Na2SO4, the solvent was removed under reduced pressure and the residue purified by chromatography over silica gel (CH2Cl2:MeOH=99:1) to yield 3.6 g (84.1%) product as a beige foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:27])[CH2:13][CH:12]([C:14](OCC)=[O:15])[S:11][C:10]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>O1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([CH2:14][OH:15])[S:11][C:10]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CC(C)(c2cccc(Br)c2)N=C(NC(=O)OC(C)(C)C)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(Br)c2)C[C@@H](CO)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
To a 0° C. solution of ethyl 4-(3-bromophenyl)-2-(tert-butoxycarbonylamino)-4-methyl-5,6-dihydro-4H-1,3-thiazine-6-carboxylate (2.0 g, 4.4 mmol) in tetrahydrofuran (87 mL) and ethanol (25 mL) is added lithium borohydride (289 mg, 13.1 mmol, 3 equiv). The reaction is warmed to room temperature and stirred for 4 h. The reaction mixture is quenched with saturated NH4Cl. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous NaCl and dried over Na2SO4. The mixture is filtered and concentrated to give a light yellow oil. The oil is purified by column chromatography on silica gel (120 g) using a gradient of 0 to 100% ethyl acetate/hexane to give the title compound (29% yield): MS (m/z): 415, 417 (M+1).
Reaction SMILES: FC(F)(F)[C:3]([O-])=[O:4].[OH:8][C@H:9]1[CH2:14][NH:13][C@@H:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1.O=C(Cl)OC(Cl)(Cl)Cl>ClCCl>[O:4]=[C:3]1[N:13]2[CH2:14][C@H:9]([CH2:10][CH2:11][C@@H:12]2[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[O:8]1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@H]1CC[C@@H](O)CN1
Reactant: O=C([O-])C(F)(F)F
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@H]1CC[C@H]2CN1C(=O)O2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.802 g (2.034 mmoles) of the trifluoroacetate of cis(4-nitrophenyl)methyl 5-hydroxy-2-piperidinecarboxylate (described in Rec. Trav. Chim. (1959), 78, 648-658), of molecular formula C13H16N2O5,CF3CO2H (M=394.303 g) is introduced under a nitrogen atmosphere, into 40 ml of dichloromethane and the reaction medium is cooled down to 0° C. 0.135 ml of diphosgene is added. Agitation is carried out for 15 minutes at 0° C., the temperature is left to rise to ambient temperature and agitation is continued for 35 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]2[NH:7][C:8](=[O:35])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([O:24][C:25]5[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[C:27]([CH3:34])[CH:26]=5)[N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.CO.[H][H]>C1COCC1.[Pd]>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]2[N:21]=[CH:20][N:19]=[C:18]([N:15]3[CH2:14][CH2:13][CH:12]([N:9]4[CH2:10][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:37]=[CH:36][C:6]=5[NH:7][C:8]4=[O:35])[CH2:17][CH2:16]3)[CH:23]=2)=[CH:26][C:27]=1[CH3:34]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc([N+](=O)[O-])c(C)c4)ncn3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4ccc(N)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
930 mg (1.84 mmol) 7-methoxy-3-(1-(6-(3-methyl-4-nitrophenoxy)pyrimidin-4-yl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one were placed in 20 mL THF and 20 mL MeOH and hydrogenated under a hydrogen atmosphere with the addition of 150 mg Pd/C (10%) at RT and a hydrogen pressure of 3 bar until all the hydrogen had been taken up. The catalyst was filtered off. Everything was distilled off from the filtrate to leave a residual volume of 15 mL. DIPE was added. The precipitate was suction filtered, washed and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:19][CH2:20][CH2:21]Cl)[S:10]2(=[O:24])=[O:23])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][NH2:26].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]([CH2:19][CH2:20][CH2:21][NH:26][CH3:25])[S:10]2(=[O:23])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN
Reactant: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccc(F)c(Cl)c1
Agent: Cl
Product: CNCCCN1Cc2ccccc2N(c2ccc(F)c(Cl)c2)S1(=O)=O

Procedure:
In an analogous manner to Example 1, step 8, 1-(3-chloro-4-fluorophenyl)-3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (73 mg) was reacted with methylamine and then treated with HCl to provide 3-[1-(3-chloro-4-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylpropan-1-amine hydrochloride (61 mg):
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[N:30]1([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][N:5]2[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[CH:8][C:7]=3[N:16]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: C1COCCN1
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reaction time: 3 h
Yield: 98.8 %

Procedure:
A modification of the method described in Part F of Example 6 was used to treat 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid (5.14 g, 16.5 mmol) with oxalyl chloride (2.59 mL, 29.7 mmol) and morpholine (4.33 mL, 49.5 mmol). The oxalyl chloride addition was carried out at ambient temperature, and the reaction with morpholine was complete in three hours. Following the work-up procedure, 6.2 g of 1-(5-morpholin-4-yl-5-oxopentyl)-2-propyl-1H-imidazo[4,5-c]quinoline were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=3[N:23]=[CH:22]2)=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][CH:34]([CH3:39])[CH2:35][CH:36]([NH2:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:33][CH:34]([CH3:39])[CH2:35][CH:36]([NH:38][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[N:21]([CH2:20][C:17]3[CH:16]=[CH:15][C:14]([C:9]4[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:19][CH:18]=3)[CH:22]=[N:23][C:24]=2[CH:29]=1)=[O:31])[CH3:37]
Reactant: CC(C)CC(C)N
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2cnc3cc(C(=O)O)ccc32)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: ClCCl
Product: CC(C)CC(C)NC(=O)c1ccc2c(c1)ncn2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The mixture of 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid (45 mg, 0.105 mmol), 4-methylpentan-2-amine (12.7 mg, 0.126 mmol), HATU (78 mg, 0.315 mmol) and DIPEA (27 mg, 0.315 mmol) in 10 mL of DCM was stirred at RTovernight. Then the solvent was removed under the reduced pressure to give the residue which was purified with prep-TLC (hexane/EtOAc=1/1, silica gel) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: Cc1cccc2c1NC(=O)C2(C)C
Reactant: ClCCOC1CCCCO1
Product: Cc1cccc2c1N(CCO)C(=O)C2(C)C

Procedure:
Prepared from 3,3,7-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.