Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]([C@H:10]([CH3:13])[CH:11]=[CH2:12])[C:7]([OH:9])=[O:8])=O.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O>[CH2:22]([O:21][C:19]([NH:5][C@@H:6]([C@H:10]([CH3:13])[CH:11]=[CH2:12])[C:7]([OH:9])=[O:8])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C[C@@H](C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C[C@@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A mixture of 25.16 g (112 mmol) of (2S,3R)-2-trifluoroacetylamino-3-methyl-4-pentenoic acid and 112 mL of 2 N aqueous sodium hydroxide is stirred at 80° C. for 1.5 h. The mixture is then allowed to cool to 25° C. and is further chilled to 0° C. 2 N aqueous sodium hydroxide (112 mL) is added followed by dropwise addition of 18 mL (126 mmol) of benzyl chloroformate. After 45 min at 0° C. and 5 h at 25° C. the mixture is added to 150 mL of water and is treated with aqueous sodium hydroxide until an orange solution resulted. The mixture is extracted with ether. The aqueous phase is acidified with 6 N HCl to pH 1 and is extracted with ether. Drying over magnesium sulfate and concentration in vacuo affords 22.61 g (77%) of (2S,3R)-2-benzyloxycarbonylamino-3-methyl-4-pentenoic acid as an oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C([N:15](CC)CC)C.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[N-:15]=[C:5]=[O:11].[CH3:22][CH2:21][O:20][CH2:24][CH3:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: [N-]=C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In reaction 1 of Scheme 1, the compounds of formula A-1 or A-2 are converted to the corresponding compounds of Formula II, wherein f is 1 to 8, or III, respectively, by adding triphosgene to a suspension of C-1 or C-2 and triethylamine in a aprotic solvent, such as tetrahydrofuran. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and a small amount of ether was added. The triethylammonium salt generated is filtered off. Separately, sodium hydride is added to a suspension of A-1 or A-2, wherein X is OH or NH, in an aprotic solvent, such as tetrahydrofuran, at 0° C. or room temperature. The reaction is stirred at room temperature for a time period between about 5 minutes to about 20 minutes, preferably about 15 minutes, and the isocyanate tetrahydrofuran/ether solution so formed above is added dropwise. Alternatively, the compounds of Formula II and III may be formed by reacting the compounds of D3 or D4 with A-1 and A-2 in presence of a base such triethylamine and diphenylphosphoryl azide in aprotic solvent such toluene as described in procedure discussed above in reaction 4 of Preparation D.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH:17][C:18](=[O:25])[CH:19]([Br:24])[CH2:20][CH2:21][CH2:22]Br)[C:13]([I:26])=[C:12]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:11]=1[I:41])=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:4][CH:5]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([Br:24])[C:18]2=[O:25])[C:13]([I:26])=[C:12]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:11]=1[I:41])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8a (20.7 g, 18.5 mmol) in N,N-dimethylacetamide (200 ml), was added powdered potassium carbonate (20 g, 92 mmol) and the mixture was stirred at room temperature for 5 hours. The resulting slurry was filtered and the filtrate freed of the solvent to obtain a light brown solid, which was redissolved in ethyl acetate (500 ml). The solution was washed with water (2×50 ml) and saturated aqueous sodium chloride (1×100 ml) and then dried over magnesium sulfate. The solvent was removed in vacuo and the crude product (18.1 g) purified by column chromatography over silica gel to obtain pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-(3-bromo-2-oxo-1-piperidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white solid (14.04 g, 80% yield), m.p. 232°-35°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[N:32]=[N:31][C:30]([NH2:33])=[CH:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[N:32]=[N:31][C:30]([NH2:33])=[CH:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)nn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)nn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and commercially available 6-bromo-3-pyridazinamine (226 mg, 1.3 mmol) according to general procedure II. Obtained as a light brown solid (270 mg, 60%). MS (ISP) 449.2 [(M+H)+]; mp 214-216° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35](Cl)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:34]([C:35]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)=[O:36])=[C:33]([CH3:38])[O:32][N:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCO)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)OCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme, C2 (TEA) using N-{3-[1-(3-hydroxypropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 524.2 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=4)=[CH:36][CH:35]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (90 mg), 4-(4-pyridyl)benzoic acid (52 mg), triethylamine (35 mg) and HOBt (39 mg) in DMF (10 ml) was added WSC hydrochloride (55 mg) under ice-cooling and the solution was stirred at room temperature 4 hours and concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated, and the residue was crystallized with ether to give colorless crystals of the title compound (122 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13]([OH:16])=[N:14][CH:15]=1.CS(O[CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=2)[CH2:25][CH2:24]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([O:16][CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=3)[CH2:25][CH2:24]2)=[CH:12][N:11]=1
Reactant: CSc1ccc(-c2cnc(O)cn2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(-c2cnc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
A mixture of 5-[2-fluoro-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) (0.35 g, 1.48 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 0.61 g, 2.0 mmol) and K2CO3 (0.42 g, 2.96 mmol) in DMF (14 mL) was stirred at 100° C. in a preheated oil bath for 5 h. The mixture was cooled to ambient temperature, treated with water, and the mixture was extracted with EtOAc (70 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid, which was purified by chromatography on a silica gel column eluted with 1:25 acetone/CH2Cl2 to give 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyrazine (0.3 g, 44% yield) as a light beige solid. 1H NMR (400 MHz, CDCl3): δ 8.54 (s, 1H), 8.28 (d, 1H, J=1.3 Hz), 7.86 (t, 1H, J=8.3 Hz), 7.10 (dd, 1H, Ja=8.3 Hz, Jb=1.7 Hz), 7.00 (dd, 1H, Ja=12.1 Hz, Jb=1.9 Hz), 4.30-4.20 (m, 4H), 3.20-3.05 (m, 2H), 2.92 (septet, 1H, J=7.0 Hz), 2.50 (s, 3H), 2.20-2.05 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.29 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 444 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:8])=[O:7].Cl.CN([CH:25]=[C:26]1[C:37]2[C:29](=[CH:30][CH:31]=[C:32]3[C:36]=2[S:35][CH:34]=[N:33]3)[NH:28][C:27]1=[O:38])C>CO.[Pd]>[OH:1][CH2:2][C:3]([CH3:20])([CH3:19])[CH2:4][NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH:25]=[C:26]2[C:37]3[C:29](=[CH:30][CH:31]=[C:32]4[C:36]=3[S:35][CH:34]=[N:33]4)[NH:28][C:27]2=[O:38])=[CH:12][CH:11]=1)(=[O:8])=[O:7]
Reactant: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=C1C(=O)Nc2ccc3ncsc3c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient temperature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s,1 H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: [NH2:1][C@H:2]([CH2:25][CH3:26])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[C:16]([CH3:24])=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[N:10][CH:11]=1)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:25]([C@H:2]1[NH:1][C:28](=[O:30])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[C:16]([CH3:24])=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[N:10][CH:11]=2)[C:3]1=[O:4])[CH3:26]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1cnc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a solution of (2R)-2-amino-N-[2-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyrimidin-5-yl]butanamide (Intermediate 21, 24 mg, 0.068 mmol) in dry DCM (3 ml) TEA (0.028 ml, 0.2 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (15 mg, 0.05 mmol) in dry DCM (1.5 ml) was slowly added and the reaction mixture was stirred for 15 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 75:25 to cyclohexane/ethyl acetate 25:75 as eluents affording the title compound (11 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)[Cl:9]>C(O)C>[Cl:9][CH2:8][CH:10]([OH:12])[CH2:11][N:1]([CH2:11][CH:10]([OH:12])[CH2:8][Cl:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: ClCC1CO1
Solvent: CCO
Product: OC(CCl)CN(CC(O)CCl)c1ccccc1
Yield: 75 %

Procedure:
1.0 mol of aniline and 2.4 mol of epichlorohydrin are heated in 375 ml of ethanol for 16 h under reflux. The solvent is then removed in vacuum and the residue introduced drop by drop into n-hexane. The crystals obtained are filtered off and dried (yield: 75%); MP: 60° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=O)[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:37]>O1CCCC1.B>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH2:20][CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CC(c1ccccc1)c1ccccc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCCC(c1ccccc1)c1ccccc1

Procedure:
To the suspension of 11.2 g of dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylpropionamido)-propane in 200 ml of tetrahydrofuran, 150 ml of 1 molar borane in tetrahydrofuran are added dropwise while stirring under nitrogen at 0°. The mixture is refluxed overnight, cooled to 0° and treated dropwise with 150 ml of methanol, followed by 30 ml of concentrated hydrochloric acid. The mixture is evaporated, again treated with 150 ml of methanol, warmed to 50° and evaporated. The resulting white solid is recrystallized from isopropanol containing a little methanol to afford the dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylpropylamino)-propane hydrochloride, melting at 187°-190°.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:15])[CH2:9][O:10][C:11](=[O:14])[CH:12]=[CH2:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:16][CH:17]1[CH2:19][NH:18]1>>[OH:15][CH:8]([CH2:9][O:10][C:11](=[O:14])[CH2:12][CH2:13][N:18]1[CH2:19][CH:17]1[CH3:16])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=CC(=O)OCC(O)COC(=O)C(=C)C
Reactant: CC1CN1
Product: C=C(C)C(=O)OCC(O)COC(=O)CCN1CC1C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a 250 mL round bottomed flask were added 3-(acryloyloxy)-2-hydroxypropyl methacrylate (32.1 g, 0.15 mol, available from Aldrich, cat. 454982) and 2-methylaziridine (10.8 g, about 0.17 mol, 90% pure, available from Aldrich). The reaction flask was cooled briefly in an ice bath and then allowed to stand at room temperature overnight. Excess 2-methylaziridine was removed at reduced pressure to leave the desired product (40.4 g) as a colorless liquid. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2>>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCCCC1
Yield: 83.6 %

Procedure:
Using an analogous procedure to that described in Example 237, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.65 g, 4.89 mmol), (prepared as described for the starting material in Example 67), was reacted with 4-fluoro-5-hydroxy-2-methylindole (970 mg, 5.88 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (1.9 g, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].Cl.[NH2:35][CH:36]1[CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1.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>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:35][CH:36]4[CH2:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH2:37]4)=[CH:23][C:22]=3[O:30][CH3:31])(=[O:19])=[O:20])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: NC1Cc2ccccc2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC2Cc3ccccc3C2)cc1OC
Yield: 70.4 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 100 starting from 0.8 g of the compound obtained in EXAMPLE 13, 0.35 g of 2-aminoindane hydrochloride, 0.8 g of BOP, 2 ml of DIPEA and 20 ml of DCM. It is chromatographed on silica using a DCM/AcOEt mixture (96/4; v/v) as the eluent to give 0.7 g of the expected product in the form of white crystals. M.p.=160° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][C:10]2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[O:8][CH2:7]1)=[O:5])C>C(O)C.[OH-].[Na+]>[CH3:17][O:16][C:15]1[C:9]2[O:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][C:10]=2[C:12]([N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1COc2c(OC)ccc([N+](=O)[O-])c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c2c1OCC(C(=O)O)C2
Yield: 92.2 %

Procedure:
A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in ethanol (150 nL) and 2 M NaOH (15 mL) was heated to reflux for 30 min. The solvent was evaporated in vacuo the residue dissolved in water. Acidification to pH 2 and extraction with ethyl acetate followed by evaporation of the solvent in vacuo gave 4.9 g (94% yield) of the title compound: mp 181-183° C.; EIMS (70 eV) m/z (relative intensity) 253 (55, M+).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([O:40]C(C)(C)C)=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([OH:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)CBr
Product: O=C(O)CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
[(2S)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetic acid was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and tert-butyl bromoacetate using the same methods as described by Procedure I.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:10]([C:9]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccncc1N
Reactant: CCCCC(=O)O
Product: CCCCc1nc2cnccc2[nH]1
Temperature: 70 °C
Yield: 99.6 %

Procedure:
A mixture of 3 g of 3,4-diamino-pyridine and 8.28 g of valeric acid was heated to 70° C. for 18 hours and the reaction medium was chromatographed on silica (eluant: ethyl acetatemethanol (8-2)) to obtain 4.8 g of the expected product which was used as is for the following step.