Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:9][CH2:8][CH2:7][O:6][C:5]1[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: OCCOc1ccc(Br)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 12.0 g (55.4 mmol) 2-(4-bromophenoxy)ethanol, 100 ml dry methylene chloride and 5.1 g (60.9 mmol) dihydropyran is added, at RT, 0.42 g (2.2 mmol) p-toluenesulfonic acid.water. The mixture is stirred for 3 days at RT, after which 50 ml methylene chloride, 50 ml water and 10 ml aqueous 15% potassium carbonate are added. The organic phase is separated and washed with water (60 ml) and with saturated aqueous sodium chloride, and is then dried over calcium sulfate. Solvent is removed by rotary evaporation to yield 4-(2-tetrahydropyranyloxyethoxy)bromobenzene.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[CH:11]=[CH:10][N:9]=N[C:7]=2[O:6][CH2:5]1.[CH:13]1([C:16]2N=CC=C3C(=O)COC=23)[CH2:15][CH2:14]1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[C:16]([CH:13]3[CH2:15][CH2:14]3)[N:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1
Reactant: CON=C1COc2nnccc21
Reactant: O=C1COc2c1ccnc2C1CC1
Product: CON=C1COc2c1ccnc2C1CC1

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 7-cyclopropylfuro[2,3-c]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (9/1) gives the desired product as brown oil;
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26]1>>[F:15][C:16]1[CH:17]=[C:18]([C:19]([N:6]2[CH:7]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:25][CH:26]=3)[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:20])[CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: O=C(c1cccc(F)c1)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
(3-Fluoro-phenyl)-[6-(1H-indol-3-yl)-6H-phenanthridin-5-yl]-methanone was prepared from phenanthridine, 3-fluorobenzoyl chloride, and indole according to GP 2. Yield, 41%. 1H-NMR (DMSO-d6): δ=6.21 (d, J=1.9 Hz, 1H), 6.41 (s, br., 1H), 6.84 (t, J=7.5 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H), 6.99-7.11 (m, 3H), 7.14 (ddd, J=J=7.7 Hz, J=0.8 Hz, 1H), 7.17-7.35 (m, 4H), 7.43 (ddd, J=J=7.4 Hz, J=1.1 Hz, 1H), 7.54 (“t”, J=7.2 Hz, 2H), 7.85 (“d”, J=7 Hz, 1H), 7.97 (dd, J=7.9 Hz, J=1.2 Hz, 1H), 8.11 (d, J=7.5 Hz, 1H), 10.71 (s, br., 1H); (+)-ESI-MS: m/z=419 [M+H]+, 302 [M−indole+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:17]1[N:18]=[C:19]([NH:36][C:37]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=2[C:39]([NH2:41])=[O:40])[C:20]2[CH:25]=[CH:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:21]=2[N:22]=1.Cl.O1CCOCC1.[NH4+].[OH-]>FC(F)(F)CO.C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10]([NH:13][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:38]=4[C:39]([NH2:41])=[O:40])[C:20]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)(=[O:27])=[O:28])[C:21]=4[N:22]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1N)N(C(C)=O)CC2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: OCC(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(C)=O)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A slurry of 1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine (212 mg, 2 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (836 mg, 1.8 mmol), KI (5.6 mg, 0.03 mmol) in 2,2,2-trifluoroethanol (10 mL) was treated with a 4 N HCl solution in dioxane (1.8 mL, 7.2 mmol). The reaction mixture was heated at 80° C. overnight in a sealed vessel, then was allowed to cool to rt Half of the reaction mixture was diluted with THF (100 mL) and a 27% aqueous NH4OH solution (100 mL). After stirring at rt overnight the reaction mixture was concentrated to dryness. The residue was sonicated in CH2Cl2 (10 mL), then filtered. The filtrate was purified by silica gel chromatography using 8-10% THF/CH2Cl2 to obtain 2-({2-{[1-acetyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide as a yellow solid (192 mg, 34% for 2 steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 3H), 2.35 (s, 3H), 3.19 (t, J=8.33 Hz, 2H), 3.73 (s, 3H), 4.15 (t, J=8.33 Hz, 2H), 6.50 (d, J=3.85 Hz, 1H), 6.92 (t, J=9.25 Hz, 1H), 7.04 (s, 1H), 7.15-7.40 (m, 4H), 7.90-7.99 (m, 3H), 8.02 (s, 1H), 8.10 (d, J=8.61 Hz, 1H), 8.16 (s, 1H), 8.24 (s, 1H), 10.49 (s, 1H); ESIMS (M+H)+=630.13.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1.C1N=CN([C:18]([N:20]2C=N[CH:22]=[CH:21]2)=[O:19])C=1.NC1C2[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C=O)C>[O:36]=[C:34]1[NH:35][C:30]2[CH:29]=[CH:28][CH:27]=[C:21]([NH:20][C:18]([NH:1][CH2:2][C:3]3[CH:4]=[N:5][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:7][CH:8]=3)=[O:19])[C:22]=2[O:32][CH2:33]1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)nc2)N1
Temperature: 70 °C
Yield: 42 %

Procedure:
To a solution of 3-aminomethyl-6-trifluoromethylpyridine (1 g, 4.7 mmol) in THF (30 mL) was added CDI (2.1 mol eq) and the mixture was heated at 70° C. overnight. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure. The oil obtained (0.8 g, 2.96 mmol) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.47 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (100% EtOAc) to obtain the product as a pale yellow solid (0.37 g, 42% Yield). 1HNMR (DMSO, 200 MHz) δ 4.39 (d, 2H, J=6), 4.61 (s, 2H), 6.46 (dd, 1H, J=2), 6.81 (t, 1H, J=8), 7.43 (t, 1H), 7.68 (dd, 1H, J=2), 7.90 (m, 2H), 8.18 (s, 1H), 8.69 (s, 1H), 10.66 (s, 1H). [M+1] 355.88 (C15H13F3N3O3 requires 355.27).
Reaction SMILES: [CH3:1][N:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([OH:8])=O.[CH2:24]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28].N12CCCN=C1CCCCC2>CN(C)C=O>[CH2:24]([S:29]([NH:32][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:3]([N:2]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH3:1])[CH:4]=1)(=[O:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCS(N)(=O)=O
Reactant: CN(Cc1ccc(Cl)cc1Cl)c1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(N(C)Cc2ccc(Cl)cc2Cl)c1
Reaction time: 1 h
Yield: 51.8 %

Procedure:
N,N′-carbonyldiimidazole (0.776 g) was added to a mixture of 0.85 g of 3-(N-methyl-2,4-dichlorobenzylamino)-4-nitrobenzoic acid and 10 ml N,N-dimethylformamide at room temperature, and the mixture was stirred for 1 hour. 1-Pentanesulfonamide (0.724 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.729 g) were then added thereto, and the resulting mixture was stirred at 100° C. for 21 hours. The mixture was concentrated, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, concentrated, and purified by silica-gel column chromatography (eluent: a mixture of hexane and ethyl acetate at a ratio of 1:1 to 0:1). The desired fractions were collected and concentrated. The concentrate was re-dissolved in ethyl acetate, washed twice with diluted hydrochloric acid and subsequently with a solution of sodium hydrogen carbonate. The organic layer was dried and concentrated to give 0.605 g of N-(n-pentanesulfonyl)-3-(N-methy-2,4-dichlorobenzylamino)-4-nitrobenzamide. This product was used immediately in the next reaction step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][CH2:42][CH2:43][C:44]#[N:45].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:21](=[O:22])[N:41]([CH2:42][CH2:43][C:44]#[N:45])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])[CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: N#CCCNc1ccccc1F
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC#N)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.6 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.090 ml) and DMF (0.001 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.059 g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 1.5 h then a solution of 3-(2-fluoro-phenylamino)propionitrile (0.026 g) in dichloromethane (1 ml), DMAP (0.002 g) and DIPEA (0.078 m l) were added. The reaction mixture was stirred at room temperature for 66 h. The reaction mixture was partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with further 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (4:1 v/v), to give the title compound as a colourless gum (0.028 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](O)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(#N)C>C(O)C(N)(CO)CO.Cl>[C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 88 %

Procedure:
Ten (10) U of the enzyme of the present invention was added in 100 mM Tris-HCl buffer (pH 7.0) to L-lysine hydrochloride (final concentration of 1 M) and lauric acid (final concentration of 15 mM), and reacted for 3 hours at 45° C. The reaction solution was analyzed by HPLC (YMC-Pack ODS 150×4.6 mm, eluent: 35% acetonitrile solution, pH 2.8, flow rate: 0.8 mL/min). The synthesis yield was about 88% based on fatty acids.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:19][C:20]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].C(Cl)Cl.Cl>N1C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([O:29][C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:18][CH:17]=2)[CH:26]=[CH:25][C:21]=1[C:22]([OH:24])=[O:23]
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)c1ccc(O)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)c(F)c2)cc1
Yield: 78 %

Procedure:
4-Octyloxybenzoic acid chloride (10.74 g) and 6.24 g of 2-fluoro-4-hydroxybenzoic acid were stirred in 20 ml of pyridine and 50 ml of methylene chloride for 3 hours on refluxing by heating. After the reaction mixture was left to cool, it was neutralized with 10% hydrochloric acid, and the precipitated crystals were separated by filtration, and washed with water and then with cold methanol. The resulting crude crystals were recrystallized from ethanol to obtain 12.11 g of 2-fluoro-4-(4-octyloxybenzoyloxy)benzoic acid (yield 78%) which was liquid crystalline (transition temperatures: m.p. 147° to 148° C., N-I point 217° C.).
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:18])=[CH:8][C@H:9]2[C:14]([O:16]C)=[O:15])[CH:2]=[CH2:3].[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:18])=[CH:8][C@@H:9]2[C:14]([OH:16])=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@@H]2C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,5R)-methyl 6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxylate (Intermediate 30, 0.479 g, 1.90 mmol) in THF (10 mL) and water (5 mL) at 0° C. was added lithium hydroxide (0.045 g, 1.90 mmol). The reaction was stirred at 0° C. for 2 hours. Another 0.5 eq lithium hydroxide was added. After 2 hours the reaction mixture was neutralized carefully with 1N HCl at 0° C. and the THF was evaporated. The aqueous was frozen and lyophilized to afford a light orange solid (0.464 g, 103% crude).
Reaction SMILES: C([NH:4][C:5]1[N:9]([C:10](=[N:24][O:25][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[N:8]=[C:7]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:6]=1)(=O)C.O.NN>[Ni]>[S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)([O-:28])(=[O:27])=[O:25].[NH3+:13][CH2:12][CH2:11][CH:10]1[N:24]=[N:4][C:5]2=[CH:6][C:7]([C:36]([CH3:39])([CH3:38])[CH3:37])=[N:8][N:9]12
Reactant: CC(=O)Nc1cc(C(C)(C)C)nn1C(CCN1C(=O)c2ccccc2C1=O)=NOS(=O)(=O)c1ccc(C)cc1
Agent: [Ni]
Agent: NN
Solvent: O
Product: CC(C)(C)c1cc2n(n1)C(CC[NH3+])N=N2
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 58.6 %

Procedure:
Analogous to example 3, synthesis step 3, using 2.49 g (4.5 mmol) of 5-acetamido-3-tert.butyl-1-(3-phthalimido-O-tosyl-propanehydroximoyl)-pyrazole and 2.5 ml 80% strength hydrazine hydrate. Decomposition of excess hydrazinc hydrate was performed using Raney nickel. 1.0 g (63%) of 3-(2-ammonio-ethyl)-6-tert.butyl-pyrazolo[5,1-c]-[1,2,4]triazole tosylate with a m. pt. of 231°-240° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:26][NH2:27]>C(O)C>[CH3:26][NH:27][C:20]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:21]
Reactant: Cc1ccc(-n2nc(C(=O)Cl)cc2-c2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of 1-(4-methylphenyl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid chloride in ml of CH2Cl2 is added dropwise to 100 ml of a 33% solution of methylamine in ethanol. After stirring for hours at room temperature, the mixture is concentrated under vacuum, the residue is taken up with a mixture of 5% Na2CO3 +AcOEt, the organic phase is decanted, washed with a saturated solution of NaCl and dried over MgSO4 and the solvents are evaporated off. The residue is taken up in isopropyl ether and the crystals obtained are filtered off and dried under vacuum to give 0.44 g of the expected amide.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:29]=[C:30]([CH3:37])[C:31]3[O:35][CH2:34][CH2:33][C:32]=3[CH:36]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[CH3:37][C:30]1[C:31]2[O:35][CH2:34][CH2:33][C:32]=2[CH:36]=[C:28]([C:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]4[C:17]5[C:12](=[N:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]4=[O:18])[CH2:7][CH2:8]3)[CH:21]=2)=[O:27])[CH:29]=1.[CH:10]([O-:18])=[O:27]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2c1OCC2
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.11 g (0.36 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 90 mg (0.23 mmol) (6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone and 0.20 mL (1.16 mmol) DIPEA were combined in 1.5 mL DMF and stirred for 48 h at RT. Then the reaction mixture was mixed with a few drops of hydrochloric acid and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][C:20]4([O:27][C:26]5[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=5[N:24]5[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=[C:23]45)[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:2]1.CC(O)C.C(=O)=O>CO>[O:1]1[CH2:5][CH2:4][C@H:3]([S:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:18][CH2:19][C:20]4([C:23]5=[CH:34][CH:33]=[C:32]([C:35]([F:37])([F:36])[F:38])[N:24]5[C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[O:27]4)[CH2:21][CH2:22]3)=[O:16])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:2]1
Reactant: O=C(c1ccc(S(=O)(=O)C2CCOC2)cc1)N1CCC2(CC1)Oc1ccccc1-n1c(C(F)(F)F)ccc12
Agent: O=C=O
Solvent: CO
Solvent: CC(C)O
Product: O=C(c1ccc(S(=O)(=O)[C@H]2CCOC2)cc1)N1CCC2(CC1)Oc1ccccc1-n1c(C(F)(F)F)ccc12

Procedure:
(4-(Tetrahydrofuran-3-ylsulfonyl)phenyl)(1-(trifluoromethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone was subjected to chiral SFC (column: Phenomenex Lux Cellulose-2 (250×10 mm), 5 μm; mobile phase: 40% IPA w/0.2% DEA, 60% CO2; concentration: 30 mg/mL in MeOH; injection volume: 20 μA; pressure: 100 bar; detection wavelength: 254 nm) to give two peaks. For each enantiomer, the solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with aqueous 1M hydrochloric acid (1×1 mL), a saturated aqueous solution of sodium bicarbonate (1×1 mL) and a saturated aqueous solution of sodium chloride (1×1 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield [4-[(3S)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone as a yellow solid (peak 1, the stereochemistry was randomly assigned): ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes (3 min run); NMR (400 MHz, DMSO) δ 7.99 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.37-7.14 (m, 3H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=4.0 Hz, 1H), 4.53-4.36 (m, 1H), 4.33-4.19 (m, 1H), 4.08-3.94 (m, 1H), 3.91-3.58 (m, 3H), 3.56-3.16 (m, 3H), 2.19-1.82 (m, 6H) and [4[(3R)-tetrahydrofuran-3-yl]sulfonylphenyl]-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone as a yellow solid (peak 2, the stereochemistry was randomly assigned): ESI-MS m/z calc. 546.1. found 547.2 (M+1)+; Retention time: 1.93 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.99 (d, J=8.3 Hz, 2H), 7.74 (d, J=8.3 Hz, 2H), 7.57 (d, J=8.2 Hz, 1H), 7.36-7.14 (m, 3H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=4.0 Hz, 1H), 4.54-4.36 (m, 1H), 4.33-4.17 (m, 1H), 4.09-3.95 (m, 1H), 3.90-3.59 (m, 3H), 3.58-3.12 (m, 3H), 2.24-1.77 (m, 6H).
Reaction SMILES: C(O)C.[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:24][CH3:25])=[C:12]([O:16]CC3C=CC=CC=3)[CH2:13]2)[CH2:8][N:7]1[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:35][CH3:36])=[C:29]([O:37][CH3:38])[CH:28]=1)[CH3:5]>C1COCC1.[Pd]>[CH2:4]([CH:6]1[CH2:15][CH:14]2[C:9](=[CH:10][C:11]([O:24][CH3:25])=[C:12]([OH:16])[CH2:13]2)[CH2:8][N:7]1[CH2:26][C:27]1[CH:28]=[C:29]([O:37][CH3:38])[C:30]([O:35][CH3:36])=[C:31]([O:33][CH3:34])[CH:32]=1)[CH3:5]
Reactant: CCC1CC2CC(OCc3ccccc3)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC1CC2CC(O)=C(OC)C=C2CN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Pd/C (10%, 30.7 mg) was covered with THF (2.0 mL) and ethanol (2.0 mL) and stirred under an atmosphere of hydrogen (balloon pressure) for 15 min at room temperature. Then 262 (334 mg, 0.7 mmol) was added as a solution in THF (4.0 mL). The reaction mixture was stirred for 18 h at room temperature, then filtered through celite. The celite was washed with ethyl acetate (4×5 mL) and the combined filtrates were concentrated in vacuo. The residue was recrystallised from ether/dichloromethane to obtain the title compound as yellow solid (253 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 0.98 (3H, t, J 7.4, CH2CH3), 1.41 (1H, sept, J 7.0, one of CH2CH3), 1.68 (1H, sept, J 6.9, one of CH2CH3), 2.51 (1H, dd, J 16.4, 5.9, one of ArCH2CH), 2.75-2.84 (2H, m, one of ArCH2CH, CHN), 3.51-3.75 (4H, m, 2×ArCH2N), 3.80 (3H, s, OCH3), 3.83 (9H, s, 3×OCH3), 6.44 (1H, s, CH), 6.60 (2H, s, 2×CH), 6.65 (1H, s, CH). 13C NMR (100 MHz, CDCl3) δ 11.1, 23.0, 29.4, 50.8, 55.2, 55.9, 56.0, 58.3, 60.9, 105.3, 108.8, 114.6, 125.4, 126.7, 135.6, 136.5, 143.9, 144.9, 153.1. LC/MS (ES+) tr 1.03 min; m/z 388.13 ((M+H)+, 100%); MeOH/H2O 95:5 (1.0 mL/min), HPLC tr 2.58 min (>97%); CH3CN/H2O 90:10 (1.0 mL/min).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]([NH:18][C:19](=[O:27])OC3C=CC=CC=3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)[CH2:3][CH2:2]1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([NH:46][C:19]([NH:18][C:10]2[CH:11]=[C:12]([C:14]([F:15])([F:17])[F:16])[CH:13]=[C:8]([CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:9]=2)=[O:27])[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(Nc1cc(CN2CCOCC2)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(CN5CCOCC5)cc(C(F)(F)F)c4)c3)c2cc1OC

Procedure:
The procedure described in Example 138B was used to react phenyl 3-(morpholinomethyl)-5-(trifluoromethyl)phenylcarbamate described in example 151A (140 mg, 0.37 mmol) with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (77 mg, 0.25 mmol). To this solution was added diisopropylethyl amine (64 μL, 0.37 mmol) and DMAP (3.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with methanol to give 47 mg. 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.98 (s, 1H), 8.70 (s, 1H), 7.88 (d, 2H), 7.55 (m, 2H), 7.44 (m, 1H), 7.35 (s, 2H), 7.25 (m, 2H), 4.00 (s, 6H), 3.58 (s, 4H), 3.34 (s, 2H), 2.39 (s, 4H). LCMS (ESI) m/z 600 (M+H)