Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[Br:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:27](=[O:28])[CH2:26][Br:25])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: O=C(Cl)CBr
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2cc3nonc3cc2C(NC(=O)CBr)C1O
Temperature: 25 °C
Yield: 73 %

Procedure:
To a mixture of 180 mg (0.765 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 117 μl (0.842 m mol) of triethylamine and 20 ml of methylene chloride were added 73 μl (0.842 m mol) of bromoacetyl chloride with stirring at the room temperature, followed by further stirring for 1 hour. After the completion of the reaction, the precipitated crystal was filtered to obtain 199 mg of the intended compound. (yield: 73%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1ccc(Br)c(F)c1

Procedure:
The title compound, m.p. 121-122° C., was prepared in accordance with the general method of example 81a) from 4-bromo-3-fluoroaniline and methyl chloroformate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]I.[H-].[Na+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH3:32])[CH2:9][CH:10]([C:14]1[CH:15]=[CH:16][C:17]([CH2:20][O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])=[CH:18][CH:19]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](OCc1ccc(C(CNC(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)O)cc1)(C(C)C)C(C)C
Reaction time: 18 h

Procedure:
To 3-(tert-butoxycarbonylamino)-2-(4-((triisopropylsilyloxy)methyl)phenyl)propanoic acid (E203) in THF under N2 and cooled to 0° C. was added CH3I followed by NaH and the solution was warmed and allowed to stir for 18 h. The mixture was taken up in EtOAc and extracted with NH4Cl (sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-10% MeOH/CH2Cl2 gradient) gave pure 3-(tert-butoxycarbonyl(methyl)amino)-2-(4-((tnisopropylsilyloxy)methyl)phenyl)propanoic acid (E204).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[C:16](=[O:18])[N:15]([CH:19]2[CH2:21][CH:20]2[C:22]2[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=2)[CH:14]=[CH:13]3)[CH:5]=[N:4][CH:3]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:13]1[C:12]2[C:17](=[C:8]([C:6]3[CH:5]=[N:4][CH:3]=[N:2][CH:7]=3)[CH:9]=[CH:10][CH:11]=2)[C:16](=[O:18])[N:15]([CH:19]2[CH2:21][CH:20]2[C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:14]=1
Reactant: Cl
Reactant: O=c1c2c(-c3cncnc3)cccc2ccn1C1CC1c1ccc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c2c(-c3cncnc3)cccc2c(Cl)cn1C1CC1c1ccc2ccccc2n1
Yield: 7.89 %

Procedure:
Anti (+8-(pyrimidin-5-yl)-2-(2-(quinolin-2-yl)cyclopropyl)isoquinolin-1(2H)-one hydrochloride from example 240b was mixed with sodium hydrogencarbonate solution and DCM. The phases were separated and the organic phase dried. Purification by column chromatography (DCM/methanol) gave the title compound (7.89% yield) as white solid. LC-MS: m/e=425.1
Reaction SMILES: [CH:1]([P:3](=[O:12])([CH:10]=[CH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[CH3:13][NH2:14].[Cl-].[NH4+]>>[CH3:13][N:14]1[CH2:11][CH2:10][P:3](=[O:12])([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:1][CH2:2]1
Reactant: CN
Reactant: C=CP(=O)(C=C)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: CN1CCP(=O)(c2ccccc2)CC1
Yield: 98.2 %

Procedure:
A mixture of divinylphenylphosphine oxide (0.40g, 2.24 mmol) and aqueous methylamine (2.6 ml of 1M = 2.7 mmol) was heated under reflux for 30 min. The aqueous solution was cooled, saturated with ammonium chloride, and extracted with chloroform. Bulb to bulb distillation of the product at 140°/0.005 mm gave 1-methyl-4-oxo-4-phenylperhydro-1,4-azaphosphorine (0.46g, 98%), as colourless hydroscopic crystals, m.p. 115°-116°. The m.p. was not raised by recrystallization from anhydrous benzene, cyclohexane (1:3). The purity of this material was confirmed by t.l.c. (chloroform-methanol (3:1)). A freshly dried sample (80°/5 mm over P2O5) gave slightly low carbon and phosphorus values owing to rapid uptake of water prior to analysis (Found: C, 62.6; H, 7.8; P, 14.6. C11H16NOP requires C, 63.2; H, 7.7; P, 14.8%). Mol. wt. (Mass spectrum), 209. Infrared spectrum νmax (Nujol): 2820 (N--CH2), 1590, 1460 (C6H5 --P), 1410, 1380, 1320, 1265, 1170, (P=O), 1110, 1065, 990, 960, 925, 810, 760, 725, 705, 665 cm-1. N.m.r. spectrum (CDCl3): 7.82, dm, 2H (o-aromatic); 7.4-7.7, m, 3H (m- and p-aromatic); 2.6-3.3, m, 4H (methylenes); 2.36, s, 3H (methyl); 1.8-2.5, m, 4H (methylenes). A sample which had been exposed to the atmosphere for a few min showed additional broad absorption bands at 3400 and 1630 cm-1 in the i.r. spectrum, and additional sharp singlets at δ3.06 and 4.62 (exchanged by D2O) in the n.m.r. spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:21]1[CH2:30][C@@H:29]([OH:31])[CH2:28][C@@H:22]1[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20]
Reactant: COc1ccc(C)cc1C1(N2C[C@@H](O)C[C@@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@@H](O)C[C@@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 72.1 %

Procedure:
With 300 mg of the compound obtained in Step 134-1 (Isomer B) and 220 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 340 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CC([O-])(C)C.[K+].[Cl:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[CH:26][N:25]=1>CN1CCCC1=O>[Cl:23][C:24]1[CH:29]=[C:28]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([F:1])[CH:7]=2)[CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1F
Reactant: Fc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Dissolve tert-butyl N-(2-fluoro-4-hydroxy-phenyl)carbamate (10.47 g, 46.1 mmol) in N-methyl-2-pyrrolidone (NMP, 100 mL), add t-BuOK (5.67 g, 50.5 mmol) and stir at 0° C. for 30 min. Add 2-chloro-4-fluoropyridine (5.5 g, 41.9 mmol), then stir at 70° C. under N2 for 12 hrs. Quench the reaction with water, extract with EtOAc (300 mL×3), combine the organic layers, wash with brine (300 mL×2), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (11.23 g, 79.5%). MS: (M+1): 339.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1>O>[CH2:1]([NH:8][C:10]1[N:19]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[N:22]=[C:18]2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Solvent: O
Product: Fc1ccccc1-c1cn2c(NCc3ccccc3)nc3c(c2n1)CCCC3
Temperature: 100 °C

Procedure:
To 5 mL of benzylamine was added 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (150 mg) and the resulting mixture heated at 100° C. for 20 min. After 10 mL of water was added to the mixture, it was cooled and the solid that precipitated was collected. The solid was recrystallized from ethanol/water to yield 5-(N-Benzylamino)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 31), m.p. 144°-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:19]=2[N:20]=1.[H][H]>CN(C)C=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: [H][H]
Reactant: COc1cc2ncnc(Nc3nc4ccc([N+](=O)[O-])cc4s3)c2cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The crude (6,7-dimethoxyquinazolin-4-yl)-(6-nitrobenzothiazol-2-yl)amine (383 mg, 1 mmol) was dissolved in dimethylformamide (100 mL). Palladium on charcoal (106 mg, 10% Pd, 0.1 mmol Pd) was added and the air was replaced with hydrogen (1 bar). The mixture was vigorously stirred for 5 h at 80° C. and then filtered through Celite. After removal of the solvent in vacuo and subsequent drying, pure N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine was obtained as a tawny powder (202 mg, 0.57 mmol, 57%). LC/ESI-MS: m/z=354 [M+H]+; m/z=352 [M−H]−; Rt=2.15 mm.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([F:17])([F:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:16][C:14]1([F:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CC(F)(F)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3,3-difluoro-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.15 g, 0.61 mmol) in DCM/TFA (3 mL/3 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3,3-Difluoro-[1,3′]biazetidinyl as a colourless oil (0.033 g, 37%). 1H NMR (300 MHz, CDCl3): δ 3.73-3.55 (m, 8 H), 3.57-3.43 (m, 1 H), 2.77 (s, 1 H)
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.[C:23]([C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1)#[N:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([O:17][CH3:18])[CH2:15][N:14]([C:28]([C:25]4([C:23]#[N:24])[CH2:27][CH2:26]4)=[O:29])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CO[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#CC1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
A solution of (±)-6-bromo-4-((cis-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (0.30 g, 0.62 mmol) in DMF (0.5 mL), was added 1-cyanocyclopropanecarboxylic acid (0.073 g, 0.65 mmol), BOP (0.30 g, 0.68 mmol) and DIPEA (0.23 mL, 1.31 mmol). The mixture was stirred at rt for 2 h, quenched with water, stirred, filtered and rinsed with water. The brown solid was dried under vacuum to afford (±)-6-bromo-4-((cis-1-(1-cyanocyclopropanecarbonyl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (250 mg, 90% yield) as a brown solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.17 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.11 (d, J=17.8 Hz, 1H), 5.09-4.92 (m, 2H), 4.55 (br. s., 2H), 4.46-3.93 (m, 3H), 3.88-3.59 (m, 2H), 3.50 (d, J=14.1 Hz, 3H), 1.75-1.46 (m, 4H); MS (ES+) m/z: 446.1, 447.2 (M+H); LC retention time: 3.1 min (analytical HPLC Method J).
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:22]([OH:24])=[O:23])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].I[CH3:27]>CN(C)P(=O)(N(C)C)N(C)C>[C:1]1([NH:7][C:8]2([C:22]([O:24][CH3:27])=[O:23])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CI
Agent: [Na]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 62.3 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid, sodium salt in 28.4 parts of iodomethane is stirred and heated to 100° C. After cooling to 10° C, there are added dropwise 340 parts of hexamethylphosphoric triamide (slightly exothermic reaction). Upon completion, stirring is continued for 24 hours at room temperature. The reaction mixture is poured onto water (800 parts) and the product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in 2,2'-oxybispropane. The product is filtered off and crystallized from 2,2'-oxybispropane, yielding methyl 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylate; mp. 94.9° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:28][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([Cl:27])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: CN1CCCNCC1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCCN(C)CC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and 1-methyl-1,4-diazepane following the procedure outlined in Example 18, Step 2 (modifications: 40° C., 24 h). 1H NMR (400 MHz, DMSO-d6): δ 9.93 (s, 1H), 8.82 (br, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.76 (s, 1H), 3.95 (t, 2H), 3.89 (s, 3H), 2.62-2.42 (m, 8H), 2.37 (t, 2H), 2.21 (s, 3H), 1.74 (m, 2H), 1.66 (m, 2H), 1.38 (m, 4H), 1.29 (m, 2H); MS (ESI): 548.3.
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:20]([CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29]O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>>[CH2:20]([CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][O:18][C:17](=[O:19])[C@H:15]([CH3:16])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Reactant: CCCCCCCCCCCC(=O)N[C@@H](C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)N[C@@H](C)C(=O)OCC(CCCCCCCC)CCCCCCCCCC
Temperature: 130 °C
Yield: 91.1 %

Procedure:
N-Lauroylalanine (10 g) and 9.5 g of 2-octyldodecanol were charged in a 200-ml flask, and thereto was added 0.5 g of p-toluenesulfonic acid as the catalyst. The mixture was maintained at 130° C. for 3 hours for reaction. To the reaction mixture was added about 200 ml of a aqueous saturated solution of sodium hydrogen carbonate, and the resulting aqueous layer was removed. The oily layer was further washed with water. The extracted oily layer was well dried by adding 5 g of anhydrous magnesium sulfate thereto, and the magnesium sulfate was then filtered off to give 16 g (yield: 82%) of a liquid product.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)(=[O:11])=[O:10].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3]([S:9](=[O:11])(=[O:10])[NH:12][C:13]3[C:14]2=[CH:15][CH:16]=[C:17]2[C:22]=3[N:21]=[CH:20][CH:19]=[CH:18]2)=[CH:2][CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cc(Cl)ccc21
Yield: 14 %

Procedure:
In the similar fashion using route 16 general procedure 61, using 2-amino-4-chloro-N-quinolin-8-yl-benzenesulfonamide (Intermediate 292) (150 mg, 0.45 mmol), t-butyl nitrite (0.08 ml, 0.67 mmol), AcOH (1.5 ml) and THF (1.5 ml) gave the title compound (20 mg, 14%) after purification by column chromatography with DCM/MeOH (99.7:0.3) as the eluent.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[C:21](=[O:22])[CH2:20][CH2:19][NH:18][C@H:17]([CH3:23])[CH2:16]2)[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:24][C:25]1[C:26]([F:34])=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.[N-]=C=O.CN1CCOCC1>>[Cl:24][C:25]1[C:26]([F:34])=[C:27]([NH:31][C:32]([N:18]2[CH2:19][CH2:20][C:21](=[O:22])[N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[CH2:16][C@H:17]2[CH3:23])=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Reactant: O=C=Nc1cccc(Cl)c1F
Agent: Cl
Agent: [N-]=C=O
Solvent: CN1CCOCC1
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)Nc1cccc(Cl)c1F

Procedure:
In analogy to the procedure described in example 58F, (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-[1,4]diazepan-5-one dihydrochloride (example 58E) and 3-chloro-2-fluorophenyl isocyanate (but with 2.1 eq. of isocyanate and 5 eq. of 4-methylmorpholine) gave after extraction with sat. aq. sodium hydrogencarbonate solution/1 M aq. sodium hydroxide solution and dichloromethane (3 times) 0.016 g (12%) of the title compound as white foam. MS: 467.2 (MH+, 1Cl).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3].[CH3:14][S-:15].[Na+]>C(O)C>[CH3:14][S:15][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([Cl:13])([Cl:12])[Cl:11])=[N:8][CH:9]=1)[CH3:3]
Reactant: C[S-]
Reactant: CC(Br)c1ccc(C(Cl)(Cl)Cl)nc1
Agent: [Na+]
Solvent: CCO
Product: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(1-bromoethyl)-2-(trichloromethyl)pyridine (A) (0.95 g, 3.14 mmol) in ethanol (15 mL) was treated with sodium thiomethoxide (0.44 g, 6.29 mmol) portionwise at 0° C. The mixture was stirred at room temperature overnight. The solvent ethanol was then removed under a reduced pressure and the residue was re-taken into CH2Cl2 and brine. The two phases were separated and the organic layer was dried over anhydrous Na2SO4, filtered, concentrated. The residue was purified on silica gel using 5% EtOAc in hexane to give 0.57 g of the partially pure 5-[1-(methylthio)ethyl]-2-(trichloromethyl)pyridine (B) in 67% crude yield. GC-MS: mass calcd for C9H10Cl3NS [M]' 269. Found 269.
Reaction SMILES: [S:1]1[C:5]([C:6]2[O:7][C:8]3[C:9](=[C:11]([C:15]([OH:17])=O)[CH:12]=[CH:13][CH:14]=3)[N:10]=2)=[CH:4][C:3]2[CH2:18][CH2:19][CH2:20][C:2]1=2.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:8]3[O:7][C:6]([C:5]4[S:1][C:2]5[CH2:20][CH2:19][CH2:18][C:3]=5[CH:4]=4)=[N:10][C:9]=13)=[O:17])[CH2:25]2
Reactant: O=C(O)c1cccc2oc(-c3cc4c(s3)CCC4)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4cc5c(s4)CCC5)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzo[d]oxazole-4-carboxylic acid (90 mg, 0.32 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (86 mg, 0.38 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (122 mg, 0.64 mmol) and 1-hydroxybenzotriazole (86 mg, 0.64 mmol) in DMF (5 mL) was stirred under nitrogen at room temperature for 10 min, and then triethylamine (0.27 mL, 1.92 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight, and then was quenched with a saturated solution of sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and semi-preparative HPLC to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)benzoxazole-4-carboxamide (55 mg, 41%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.01 (d, J=7.5 Hz, 1H), 8.16 (dd, J=8.0, 1.0 Hz, 1H), 7.65 (s, 1H), 7.61 (dd, J=8.0, 1.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.60-4.50 (m, 1H), 3.10 (d, J=10.0 Hz, 2H), 3.03-3.00 (m, 2H), 2.86-2.82 (m, 2H), 2.65-2.52 (m, 4H), 2.54 (s, 3H), 2.18-1.96 (m, 3H), 1.62-1.46 (m, 3H), 1.25-1.18 (m, 2H); MS (ESI+) m/z 422 (M+H); HPLC>99% (AUC), tR=13.28 min.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[S:8][C:9]([C:13]2[N:14]=[C:15]([C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]4[O:25]C(C)(C)[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)=[O:19])[S:16][CH:17]=2)=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH3:4].Cl.O>C1COCC1>[C:3]([NH:6][C:7]1[S:8][C:9]([C:13]2[N:14]=[C:15]([C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([OH:25])=[C:23]([CH:22]=3)[C:28]([OH:29])=[O:27])=[O:19])[S:16][CH:17]=2)=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc4c(c3)C(=O)OC(C)(C)O4)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc(O)c(C(=O)O)c3)n2)s1
Reaction time: 0.83 h

Procedure:
Sodium hydroxide 5N solution (109 μl; 5 M; 0.55 mmol; 12.50 eq.) is added to a solution of 2′-(acetylamino)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxamide, obtained in Step I as described above (20 mg; 0.04 mmol; 1 eq.) in THF (1 ml) at rt. After 50 min, the deprotection is complete. Hydrogen chloride (109 μl; 5 M; 0.55 mmol; 12.50 eq.) is added, followed by water (2 ml). The resulting precipitate is isolated by filtration, washed with water and dried under vacuo. Compound (22) is isolated as yellow solid (14 mg; 77%).