Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[CH2:17]([C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=[CH:21][C:20]=1[F:34])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O.O1CCOCC1>[CH2:17]([C:19]1[C:20]([F:34])=[CH:21][N:22]=[CH:23][C:24]=1[C:2]1[C:3]([F:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2)[CH3:18]
Reactant: Cc1nnc2n1-c1ccc(Br)c(F)c1CC2
Reactant: CCc1c(F)cncc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CCc1c(F)cncc1-c1ccc2c(c1F)CCc1nnc(C)n1-2
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-6-fluoro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (146-7; 0.2 g, 0.00704 mol) and 4-ethyl-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.21 g, 0.0084 mol) in the mixture of 1,4-dioxan (5 mL) and water (5 mL) was added sodium carbonate (0.186 g, 0.0176 mol). Reaction mass was purged with argon for the next 20 min. Catalyst Pd(dppf)2Cl2.dichloromethane (0.28 g, 0.00352 mol) was added and again purged with argon for 10 min and allowed to stir at 100° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography followed by preparative HPLC (analytical conditions: column: ZORBAX XDB (150 mm×4.6 mm×3.5 μm), mobile phase (A): water, mobile phase (B): methanol, flow rate: 1.0 mL/min, gradient T/% B:0/20,8/70,25/70,27/20,30/20) to obtain title compound. 1H NMR (400 MHz, CDCl3-d6) δ 8.451 (s, 1H), 8.238 (s, 1H), 7.427-7.406 (d, J=8.4 Hz, 1H), 7.297-7.278 (d, J=7.6 Hz, 1H), 3.219-3.184 (t, J=6.4 Hz, 2H), 3.132-3.097 (t, J=7.6 Hz, 2H), 2.812 (s, 3H), 2.604-2.586 (d, J=7.2 Hz, 2H), 1.130-1.093 (t, J=7.6 Hz, 3H). MS (M+1): 327.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[N:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1>CCCCCC>[CH2:1]([N:8]1[C:9]2=[N:13][C:14]3[C:15]([C:16]([NH2:17])=[C:10]2[CH2:11][CH2:12]1)=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1N=C1CCCN1Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1c2c(nc3ccccc13)N(Cc1ccccc1)CC2
Temperature: -10 °C
Yield: 37.9 %

Procedure:
The compound 1-Benzyl-2,3-dihydro-1H-pyrrolo[2,3-b]quinolin-4-ylamine (Compound 25) was synthesized by first cooling a solution of Compound 24 (37.6 g, 0.14 mol) and tetrahydrofuran (350 mL) to −35° C. under argon atmosphere and adding a solution of hexane (110 mL) and lithium diisopropylamine-tetrahydrofuran complex (0.35 mol) dropwise. The temperature of the mixture was then gradually raised to −10° C. and ice-water (30 mL) was added dropwise. Organic solvent was evaporated under reduced pressure and the mixture was extracted with chloroform. The combined organic extracts were dried with anhydrous sodium sulfate and condensed under vacuum. The residue was treated with ethanol (15 mL) and crystals precipitated. The precipitate was filtered, washed with cold ethanol and dried under vacuum to yield 14.6 g (39%) of Compound 25 as needles; mp 174-176° C.; IR (KBr): 3411, 3116, 1654, 1502, 1350, 756 cm−1; 1H NMR (DMSO-d6): δ 7.01-7.93 (m, 9H), 6.05 (s, 2H), 4.60 (s, 2H), 3.37 (t, 2H), 2.87 (t, 2H); 13C NMR (CDCl3): δ 162.7, 149.3, 144.8, 138.8, 128.7, 128.2, 128.1, 127.2, 126.2, 121.8, 119.9, 117.6, 100.7, 48.4, 23.3. Anal. Calcd. for C18H17N3(275.35): C, 78.52; H, 6.22; N, 15.26. Found: C, 78.07; H, 6.07; N, 15.08.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C(OP([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Br:26])(=O)OCC)C.CC(C)([O-])C.[K+].Cl>O1CCCC1.O>[Br:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1/[CH:19]=[CH:7]/[C:6]1[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:10]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOP(=O)(Cc1ccccc1Br)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Cl)cc1/C=C/c1ccccc1Br
Yield: 81.3 %

Procedure:
5-Chlorosalicylaldehyde (188 g, 1.2 mol) was added to a solution of (2-bromo-benzyl)-phosphonic acid diethyl ester (369 g, 1.2 mol) in tetrahydrofuran (1500 ml) under nitrogen. A solution of potassium tert-butoxide (300 g, 2.68 mol) in tetrahydrofuran (3000 ml) was added while keeping the temperature at 33° C. After completion of the reaction water (1800 ml) was added followed by 4N HCl (450 ml). The organic layer was washed with sodium carbonate solution (500 ml) and saturated NaCl solution. The organic layer was evaporated under reduced pressure at 50° C. to give trans-2-bromo-5′-chloro-2′-hydroxystilbene (301.9 g, 92%).
Reaction SMILES: ClCC([NH:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][C:17]3[C:22]([N:23]=2)=[CH:21][CH:20]=[C:19]([C:24]2([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:26][CH2:25]2)[N:18]=3)=[C:11]([F:33])[CH:10]=1)([CH3:8])[CH3:7])=O.NC(N)=S>C(O)C.C(O)(=O)C.C(Cl)Cl>[F:33][C:11]1[CH:10]=[C:9]([C:6]([NH2:5])([CH3:7])[CH3:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:16][C:17]2[C:22]([N:23]=1)=[CH:21][CH:20]=[C:19]([C:24]1([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:25][CH2:26]1)[N:18]=2
Reactant: CC(C)(NC(=O)CCl)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: NC(N)=S
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
To a solution of 2-chloro-N-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)propan-2-yl)acetamide (0.51 g, 1.0 mmol) in ethanol (10 mL) and acetic acid (2 mL) was added thiourea (0.12 g, 1.58 mmol). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. ISCO purification with 1% to 10% MeOH/CH2Cl2 afforded a crude crop of the desired product. Trituration with CH2Cl2 afforded 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)-propan-2-amine as a white amorphous solid. MS (ESI) m/z: Calculated: 403.2; Observed: 404.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To a solution of 1-bromo-3,5-dimethoxybenzene (2.17 g, 10 mmol) in THF (15 mL) was dropwise added n-butyl lithium (8 mL, 2.5 mol/L in hexane, 20 mmol) at −78° C. After stirring for 50 mins at −78° C. a solution of diethyl oxalate (4 g, 27 mmol) in THE (10 mL) was added. The mixture was stirred at −78° C. for another 4 h, then quenched with saturated ammonium chloride and extracted with ethyl acetate (50 mL*3). The organic layers were combined, washed by brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel to give the title compound (1.7 g, 71%). MS (ES+) C12H14O5 requires: 238. found: 239 [M+H]+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:28][CH3:29])=[C:12]([S:19][CH2:20][CH:21](OCC)OCC)[CH:13]=2)[CH:8]=1)C.ClC1C=CC=CC=1.ClCCl>CO>[CH3:29][O:28][C:11]1[C:12]2[S:19][CH:20]=[CH:21][C:13]=2[C:14]2[CH:15]=[C:16]([O:17][CH3:18])[C:7]3[S:6][CH:5]=[CH:4][C:8]=3[C:9]=2[CH:10]=1
Reactant: CCOC(CSc1cc2cc(OC)c(SCC(OCC)OCC)cc2cc1OC)OCC
Solvent: ClCCl
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1cc2c3ccsc3c(OC)cc2c2ccsc12
Temperature: 140 °C
Yield: 64.6 %

Procedure:
2,6-Bis-(2,2-diethoxy-ethylsulfanyl)-3,7-dimethoxy-naphthalene (5.0 g, 10.3 mmol) and 6.8 g of 84% polyphorphoric acid were added into a 250 mL 3-neck flask equipped with a condenser. The system was flashed with argon for 15 minutes before 50 mL of anhydrous chlorobenzene was added. The mixture was heated at 140° C. for 40 hours before it was cooled down to room temperature. Dichloromethane (100 mL) was added. The organic mixture was washed with saturated NaHCO3 before the solvent was removed under vacuum. Methanol (100 mL) was added before 5,10-dimethoxy-1,6-dithia-dicyclopenta[a,f]naphthalene (2.0 g, ˜66% yield) was collected as a white solid by filtration, washed with methanol and dried in vacuo. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, 2H, J=5.5 Hz), δ 7.62 (d, 2H, J=5.5 Hz), δ 7.51 (s, 2H), δ 4.18 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[In].Cl>O.O1CCCC1>[N:13]1([S:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[NH2:1])(=[O:12])=[O:11])[CH2:14][CH:15]=[CH:16][CH2:17]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)N2CC=CC2)c1
Agent: Cl
Agent: [In]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)N2CC=CC2)c1
Reaction time: 24 h

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer and charged with 1-(3-nitrobenzenesulfonyl)-2,5-dihydro-1H-pyrrole (Example 92, 9.32 mmol, followed by 3:1 water/tetrahydrofuran v/v (50 mL). Indium powder (37.3 mmol) was added, followed by concentrated HCl (55.9 mmol). The reaction gives a slight exotherm and the indium forms a solid metal chunk. After 24 hours, TLC (dichloromethane/silica) indicated the reaction was mostly complete. The indium was removed with a pair of tweesers to a separate waste stream and the reaction was neutralized with sodium bicarbonate. The aqueous mixture was extracted with ethyl acetate (150 mL), the organic layer dried (Na2SO4), filtered, and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a 600 mL sintered glass funnel charged with silica gel (400 g). The silica plug was eluted with 9:1 dichloromethane:ethyl acetate, collecting 100 mL fractions. Fractions containing the desired product were combined and the solvent was removed under diminished pressure to afford 3-(2,5-dihydropyrrole-1-sulfonyl)-aniline as a white, crystalline solid. 1.50 g, (72%). m.p.: 187-188° C. LC/MS: m/z 224.8 [C10H12N2O2S+H]+. 1H-NMR (CDCl3): δ 4.0 (b, 2H); 4.13 (s, 4H); 5.66 (s, 2H); 6.84-6.87 (d, 1H, J=7.9 Hz); 7.13-7.14 (s, 1H); 7.18-7.20 (d, 1H, J=7.7 Hz); 7.26-7.31 (t, 1H, J=7.8 Hz).
Reaction SMILES: C(OC(C1CC[N:11]([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)CC1)=O)(C)(C)C.[C:31]([O-:34])(=[O:33])C.[NH4+:35]>CO>[C:21]([O:34][C:31]([N:35]1[CH2:23][CH2:24][CH:19]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:28])[F:29])[CH:20]=3)[N:11]=2)[CH2:17][CH2:16]1)=[O:33])([CH3:26])([CH3:22])[CH3:20]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Reactant: CC(=O)[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)c[nH]2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 114.3 %

Procedure:
Combine 1-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethylcarbamoyl]-piperidine-4-carboxylic acid tert-butyl ester (100 g, 231 mmoles), ammonium acetate (178.3 g; 2.31 moles, 10 eq), and methanol (1000 mL). The reactor used for this transformation is a coiled 1/16″ I.D. stainless steel tube (total internal volume of tubing in oven is 541 mol). Heat the reactor in an oven to 140° C. Control the back pressure in this tube at 250 psig by a regulator to allow super-heating of the solution above its normal boiling point. Pump the solution prepared above continuously through the heated tube under pressure at 6.01 mL/min (affording a total residence time in the heated tube of 90 minutes). As the solution exits the oven, cool it back to 20° C. in a tube-in-tube heat exchanger. Once the entire solution process through the reactor (8 hours total processing time), concentrate the resulting orange solution under vacuum at 30° C. to a total volume of 600 mL. Add acetonitrile (200 mL) and heat the solution to 50° C. Add water (700 mL) drop wise with seeding over 2 hours to crystallize the product. Cool the resulting slurry to 20° C. and filter the solid, then wash with 20% MeOH in water (2×200 mL). Dry the resulting solid under vacuum at 50° C. Re-slurry the solid in acetonitrile (200 mL) at 50° C. Cool the slurry to ambient temperature, filter the solid and wash with acetonitrile (100 mL) to afford 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (54.43 g, 132 mmoles, 57%) as an off white solid.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])(C)C)(C)C.ClC[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)[CH:44]=[O:45]>CCOCC>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:44][O:45][C:12]1([OH:19])[CH:11]=[CH:10][C:9]([CH2:1][CH2:4][CH2:5][CH2:8][CH2:9][CH2:1][CH2:4][CH3:5])=[CH:18][CH:13]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: ClCCOCCOCCOC1CCCCO1
Reactant: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCC1=CC(C(=O)OC)C(O)(OCCOCCOCCOC2CCCCO2)C=C1
Temperature: 140 °C

Procedure:
A mixture of methyl 5-t-octylsalicylate (37.7 g, 0.143 mole), 2-(2-[2-(2-chloroethoxy)ethoxy]ethoxy)tetrahydropyran (54 g, 0.124 mole), potassium carbonate (28 g, 0.217 mole) and N,N-dimethylformamide (250 ml) was heated at 140° C., under nitrogen, for 18 hours, with stirring. The mixture was cooled, diluted with ether, and then washed liberally with saturated sodium chloride solution. The ethereal solution was dried (MgSO4) and evaporated in vacuo to give an oil, which was chromatographed on silica gel to give 46 g of methyl 2-(2-[2-(2-[2-tetrahydropyranyloxy]ethoxy)ethoxy]ethoxy)-5-octylsalicylate
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:21]=[C:20]([CH2:30][CH2:31][CH3:32])[N:19]=1>ClC(Cl)C>[ClH:9].[O:27]1[CH2:26][CH2:25][N:24]([C:22]2[N:21]=[C:20]([CH2:30][CH2:31][CH3:32])[N:19]=[C:18]([NH:17][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:23]=2)[CH2:29][CH2:28]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1nc(N)nc(N2CCOCC2)n1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc(NC(=O)c2ccccc2)nc(N2CCOCC2)n1
Product: Cl
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A solution of 7.7 g (0.055 mole) of benzoyl chloride in 50 ml of dichloroethane and a solution of 5.5 g (0.055 mole) of triethylamine in ml of dichloroethane are successively added into a solution of 11.2 g (0.05 mole) of 2-amino-4-morpholino-6-propyl-1,3,5-triazine in 200 ml of dichloroethane at room temperature. The mixture is heated under reflux for 6 hours and cooled to room temperature. It is washed successively with water, with an aqueous solution of sodium bicarbonate and then with water once again. The organic phase is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue obtained is chromatographed on silica (eluent: 95:5 (v/v) dichloromethane-ethanol) and finally recrystallized from a 50:50 mixture (v/v) of diethyl etherhexane. The product forms a hydrochloride in the diethyl ether. 12.1 g of N-(4-morpholino-6-propyl-1,3,5-triazin-2-yl)-benzamide hydrochloride are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:32]([NH:43][C:44]1[CH:48]=[C:47]([CH3:49])[O:46][N:45]=1)=[O:34]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: Cc1cc(N)no1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4cc(C)on4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.8 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (43 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 3-amino-5-methylisoxazole (15 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (19.0 mg, yield 32%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(COCc1ccccc1)CC(CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)C(COCc1ccccc1)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 22 h

Procedure:
A solution of 14.70 g of tert-butyl (3-benzyloxymethyl-1-hydroxymethyl-4-methylpentyl)carbamate and 0.24 g of p-toluenesulphonic acid monohydrate in 82 ml of dichloromethane at 0° C. is admixed with 8.2 ml of 2-methoxypropene. After 22 hours at room temperature, the mixture is poured onto 1M aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×)—the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.30 (gradient I).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([S:11][CH3:12])=[C:8](Br)[N:9]=1)[CH2:2][CH3:3].C1COCC1.C([Li])CCC.ClC(OCC)=O>CCCCCC.O>[CH2:1]([S:4][C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:7]([S:11][CH3:12])=[CH:8][N:9]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc(Br)c(SC)n1COCC[Si](C)(C)C
Agent: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCCSc1ncc(SC)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
7.94 g of the product obtained in Stage C above is introduced at ambient temperature into 80 cm3 of anhydrous THF, followed by cooling down to -78° C. and 13.75 cm3 of a 1.6M n-butyllithium solution in hexane is added. After 10 minutes, 15 cm3 of ethyl chloroformate is added, followed by agitation for another 15 minutes at -78° C. 60 cm3 of water is added, the reaction medium is left to return to ambient temperature, the THF is evaporated off, 10 cm3 of 32% soda is added to destroy the excess ethyl chloroformate, followed by extraction with 3×200 cm3 of AcOEt, washing with 2×80 cm3 of water, drying, filtering and evaporating.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[CH:12]([C:15]1[S:16][C:17]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][N:19]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>CC#N>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:17]3[S:16][C:15]([CH:12]([CH3:13])[CH3:14])=[N:19][CH:18]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: CC(C)c1ncc(C(=O)N2CCOC3(CCNCC3)C2)s1
Reactant: OCCCCCCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)c1ncc(C(=O)N2CCOC3(CCN(CCCCCCCCCO)CC3)C2)s1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 9-bromo-1-nonanol (0.446 g) in MeCN (3.9 mL) was added to solution of (2-isopropylthiazol-5-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 114, step b) (0.395 g) and triethylamine (0.36 mL) in MeCN (8.6 mL). The resulting mixture was stirred at 60° C. under argon for 16 h. After cooling to RT the solvent was removed in vacuo. The residue was taken up in DCM (25 mL), washed with brine (20 mL) and water (20 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to give the subtitled compound as a white solid. Yield 0.329 g.
Reaction SMILES: CN1CCN=C1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=[CH:9][CH:8]=1.[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][N:39](C2C=CC(N)=CC=2)[CH2:38][CH2:37]1.C(Cl)CCl>CN(C=O)C.O>[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][N:39]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])=[CH:11][CH:12]=2)[CH2:38][CH2:37]1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C2=NCCN2C)cc1
Reactant: CN1CCCN(c2ccc(N)cc2)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(N2CCCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 84, 40 mg, 0.13 mmol) and 4-(4-methyl-homopiperazinyl)phenylamine (61 mg, 0.25 mmol) in DMF (3 mL) and H2O (1 mL), EDC (96 mg, 0.50 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (25 mg). MS 506.2 and 508.2 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[N:3]1.[C:32](Cl)(=[O:34])[CH3:33].C(N(C(C)C)C(C)C)C>ClCCl.CO>[C:32]([N:23]1[CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:8]3[N:7]=[C:6]([C:30]#[N:31])[C:5]4[N:4]=[N:3][N:2]([CH3:1])[C:10]=4[CH:9]=3)=[CH:12][C:13]=2[C:26]([F:29])([F:28])[F:27])[CH2:25][CH2:24]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (50 mg), acetyl chloride (0.041 ml), and N-ethyl-N-isopropylpropan-2-amine (0.096 ml) were combined in dichloromethane (1 ml) and the reaction mixture stirred at room temperature for 2 hours. Washed with water the organic layer was separated, dried, and blown down to afford crude product. Solid was suspended in methanol and filtered off to afford the title compound (29.1 mg).