Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([Cl:14])[N:13]=1)=[O:7])CCC.[NH2:19][CH2:20][C:21]([OH:23])=[O:22].CO[Na].CO>>[Cl:14][C:12]1[N:13]=[C:8]([C:6]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:7])[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]=12
Reactant: CCCCOC(=O)c1nc(Cl)c2sccc2c1O
Reactant: NCC(=O)O
Agent: CO[Na]
Solvent: CO
Product: O=C(O)CNC(=O)c1nc(Cl)c2sccc2c1O
Reaction time: 24 h
Yield: 96.3 %

Procedure:
A mixture of 7-chloro-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (143 mg, 0.5 mmol), glycine (751 mg, 10 mmol), and a 0.5 M solution of MeONa in methanol (20 ml, 10 mmol) was refluxed with stirring for 24 h before it was concentrated in vacuo. To the residue was added H2O (10 ml) and the pH of the mixture was adjusted to 1 to 2 by addition of 6 N HCl. The resulting suspension was extracted with EtOAc (1×25 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (138 mg). MS-(−)-ion: M−1=285.0.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[C:14]=1[NH:22][C:23](=[O:39])[CH2:24][NH:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:12]>CCOC(C)=O>[CH3:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[C:14]=1[NH:22][C:23](=[O:39])[CH2:24][N:25]([CH:26]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])[CH3:10]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CN(C(=O)Nc1ccccc1)C(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
Excess phenylisocyanate (0.44 g) was added to a mixture of the product from Example 4 (0.60 g) in 100 mL EtOAc at room temperature. After sitting for a short period of time at room temperature, the solvent was removed in vacuo. EtOAc was added to the residue and allowed to sit 2 days at room temperature. The ethyl acetate was removed on the rotary evaporator. The residual solid was slurried in hexane/EtOAc, 1/1 and collected by filtration. (0.82 g) (100%). NMR (CDCl3) δ 1.06 (12H, d), δ 2.66 (2H, m), δ 4.24 (2H, s), δ 6.44 (1H, bs), δ 6.9-7.5 (18H, m), δ 7.93 (1H, bs). IR (KBr) 3391, 2964, 1648, 1531, 1444, 752, 700 cm-1.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=O.[OH-].[Na+]>Cl>[OH:13][C:14]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)([CH3:18])[CH3:15]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(O)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.5 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (1.5 g, 9.2 mmol) in 4 M HCl (50 mL) was added 2-hydroxyisobutyric acid (2.87 g, 27.6 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH ˜3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. The filtrate was concentrated and the residue was rinsed with ether. The remaining solid residue was dissolved in ethyl acetate, and washed with brine solution. After drying over MgSO4, the organic solution was evaporated in vacuo, yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09. found 221.1. 1H-NMR (CD3OD) δ (ppm) 7.8 (dd, 1H), 7.7 (dd, 1H), 7.2 (m, 1H), 1.3 (s, 6H).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([O:17]C)=[O:16])[N:10]=1)[CH2:3]C(OCC)=O.O.S(Cl)([Cl:23])(=O)=O>C(OCC)(=O)C>[Cl:23][CH2:3][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([OH:17])=[O:16])[N:10]=1)=[O:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1cccc(C(=O)OC)n1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cccc(C(=O)CCl)n1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
41.4 g of ethyl 3-oxo-3-(6-methoxycarbonyl-2-pyridyl)propionate was dissolved in a solution consisting of 42 ml of water and 414 ml of ethyl acetate, and the obtained solution was then cooled to a temperature between 5° C. and 10° C. Thereafter, a solution obtained by dissolving 35.6 g of sulfuryl chloride in 83 ml of ethyl acetate was added dropwise to the above cooled solution over approximately 30 minutes, while stirring. Thereafter, the obtained mixture was stirred at a temperature between 10° C. and 20° C. for 1 hour. Subsequently, the reaction solution was heated up to approximately 90° C., while the solvent was distilled away from the reaction solution. The reaction solution was continuously heated at a temperature between approximately 90° C. and 100° C. for 2 hours while stirring. Thereafter, the obtained mixed suspension (containing crystals) was cooled to approximately 10° C., and it was then stirred for 1 hour, followed by filtration, so as to obtain 27.99 g of 2-(2-chloroacetyl)-6-pyridine carboxylic acid in the form of yellow-brown crystals (melting point: 184° C. to 189° C.; purity: 98% to 99%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[CH:7]=2)[CH2:3][CH2:2]1.[H-].[Na+].[CH3:19][N:20]([CH3:23])C=O>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([O:16][CH2:15][C@H:6]([OH:5])[CH2:7][CH2:8][C:9]2[CH:23]=[N:20][CH:19]=[CH:11][CH:10]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: Oc1ccc2cc(OCC3CC3)ccc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O[C@H](CCc1cccnc1)COc1ccc2cc(OCC3CC3)ccc2c1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-cyclopropylmethoxy-6-hydroxynaphthalene (0.270 g) in anhydrous N,N-dimethylformamide (10 ml) was added dropwise to sodium hydride (60% dispersion in mineral oil, 0.457 g) that had been previously washed with isohexane (2 ml) under a nitrogen atmosphere. After stirring at 20° C. for 20 minutes a solution of (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-(4-toluenesulfonyloxy)butane (0.46 g) in anhydrous N,N-dimethylformamide (2 ml) was added and the mixture stirred at 60° C. for 90 minutes. After cooling the reaction was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (50 ml) and treated with tetrabutylammonium fluoride hydrate (0.48 g). After 1 hour the solution was diluted with water and extracted with ether. The organic extract was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (24:1) to give the title compound as a solid (0.124 g) which was recrystallised from ethyl acetate/isohexane.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:24][N:23]=1)=[O:26]
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CN
Product: CNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid and methylamine following a procedure analogous to that described in Example 168. Mass spectrum (ESI+): m/z=488 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[NH:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])[N:19]=[N:18]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[NH:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][C:25]([NH:1][CH:2]2[CH2:3][CH:4]3[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]3)[CH2:8]2)=[O:26])[N:19]=[N:18]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(N)C2
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(NC(=O)CCCc1c[nH]nn1)C2

Procedure:
A reaction mixture comprising of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.105 mmol), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (Example 17, step 4) (171 mg, 1.105 mmol), T3P® 50% DMF (1.29 ml, 2.209 mmol) and TEA (462 μl, 3.31 mmol) in DMF (3.6 ml) was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The resulting oil was diluted with DCM and washed with water. The organic portion was dried over MgSO4, filtered and concentrated under reduced pressure. The material was taken crude to the next step.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>CN(C=O)C.O>[NH2:9][C:8]1[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[S:18][C:17]=1[C:16]([O:20][CH3:21])=[O:19]
Reactant: N#Cc1ncccc1Cl
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2cccnc2c1N
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a mixture of 3-chloropyridine-2-carbonitrile (C-1) (1.01 g, 7.29 mmol) and K2CO3 (1.10 g, 7.96 mmol) in DMF (10 mL) and water (1 mL) was added methyl thioglycolate (0.709 mL, 7.93 mmol) dropwise. The reaction mixture was stirred at 40° C. for 3 h. The mixture was quenched with cold water (70 mL) and placed on ice to enhance precipitation. The precipitate was collected by filtration to afford the title compound. MS (m/z): 209 (M+1)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>>[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:23])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-methyl-3-trifluoromethyl-benzoic acid (CAS RN 261952-01-6) after a reaction time of 90 hours. Grey solid (32%). MS (ESI): m/z=385.15 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:29])[CH:20](O)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)C>[CH3:17][O:18][C:19](=[O:29])[CH:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(Cc1ccccc1)Oc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 4′-hydroxy-4-nitro-biphenyl (4.12 g, 19.1 mmol), prepared in step 2 of Example 16, 2-hydroxy-3-phenyl-propionic acid methyl ester (3.35 g, 18.5 mmol) and triphenylphosphine (4.12 g, 19.1 mmol) in diethyl ether was cooled under nitrogen to 0° C. Diisopropyl azodicarboxylate (6.09 mL, 30.96 mmol) was then added and the reaction allowed to come to room temperature and then stirred overnight at room temperature. The reaction was concentrated under reduced pressure. Purification of the residue on silica gel using 15% ethyl acetate hexanes as the eluent gave 2-(4′-nitro-biphenyl-4-yloxy)-3-phenyl-propionic acid methyl ester.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:33]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 90 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 8; 0.34 g) and sodium hydroxide (0.3 g) were dissolved in ethanol and the mixture was heated to reflux for 1 hour. Acetic acid (1 ml) was added and the solvent was removed at reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated and dried. Trituration of the residue with n-hexane gave the title compound 0.29 g (90%) as a solid. NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.7 (m, 8H), 3.1–3.2 (m, 2H), 3.6 (brs, 2H), 4.6 (s, 2H), 6.9–7.1 (m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[CH2:14][S:13][C@@H:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[S:11]1)(C(C)(C)C)(C)C>CO.C(Cl)(=O)C.[Cl-].[NH4+]>[CH2:18]([O:17][P:15]([O:20][CH2:21][CH3:22])([C@H:12]1[S:11][C@@H:10]([CH2:9][OH:8])[CH2:14][S:13]1)=[O:16])[CH3:19]
Reactant: CCOP(=O)(OCC)[C@@H]1SC[C@@H](CO[Si](C)(C)C(C)(C)C)S1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CO
Product: CCOP(=O)(OCC)[C@@H]1SC[C@H](CO)S1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of cis-4-(t-butyldimethylsilyloxymethyl)-2-(diethyloxyphosphinoyl)-1,3-dithiolane (example 49) (3.70 g, 9.56 mmol) in anhydrous methanol (50 mL) was added acetyl chloride (6 drops) at 0° C. The solution was stirred at 0° C. for 30 min and then at room temperature for 4.5 hrs. A saturated solution of ammonium chloride (3 drops) was added and the solution was stirred for 15 min followed by evaporation of solvents. The crude material was purified by flash chromatography with a mixture of dichloromethane and methanol (95:5) to give the compound (2.02 g) in 77% yield.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(OCC)(=O)C.O1CCOCC1>[ClH:31].[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nn(-c3ccccc3F)c3ccccc23)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccccc1-n1nc(OC2CCNCC2)c2ccccc21
Reaction time: 0.67 h
Yield: 55 %

Procedure:
To a stirred solution of 187 g (0.456 mole) of 4-[1-(2-fluoro-phenyl)-1H-indazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester in 600 mL of ethyl acetate was added 300 mL of 4M hydrogen chloride in dioxane dropwise over a 30 minute period. The temperature rose to 24° C. from 21° C. during the addition. When the addition was complete, gas evolution was observed and the temperature rose to 28° C. A cold water bath was used to lower the temperature to 18° C. After stirring for approximately 40 min, a solid began separating. Stirring was continued at 18-20° C. for 3 hours and then at −10° C. (ice-acetone bath) for 1 hour. The solid was collected by filtration, rinsed with 60 mL of ethyl acetate and pressed dry under suction. Further drying in vacuo at 30° C. for 16 hours afforded 87.3 g (55%) of product. The combined filtrate and washing was concentrated in vacuo to near dryness. The residue was taken up in 250 mL of ethyl acetate and the suspension was stirred at −10° C. for 2 hours. The solid was collected by filtration, rinsed with 30 mL of ethyl acetate and pressed dry under suction. Further drying in vacuo at 30° C. for 16 hours provided an additional 23.2 g (15%) of product. Total yield=110.5 g (70%). 1H NMR (CD3OD) δ ppm: 7.7 (d, 1H), 7.6 (t, 1H), 7.5-7.6 (m, 2H), 7.3-7.5 (m, 2H), 7.25 (m, 1H), 7.2 (t, 1H), 5.2 (m, 1H), 3.4-3.5 (m, 2H), 3.2-3.3 (m, 2H), 2.3-2.4 (m, 2H), 2.2-2.3 (m, 2H).
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([CH2:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])(=[O:15])=[O:14])[CH2:9]2)C=CC=CC=1.[H][H].[ClH:31]>C(O)C.O.[OH-].[OH-].[Pd+2]>[ClH:31].[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([CH2:12][CH:10]1[CH2:11][NH:8][CH2:9]1)(=[O:14])=[O:15]
Reactant: O=S(=O)(CC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1F
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S(=O)(CC1CNC1)c1ccccc1F
Yield: 91 %

Procedure:
1-(Diphenylmethyl)-3-{[(2-fluorophenyl)sulfonyl]methyl}azetidine (1.33 g, 3.37 mmol) was dissolved in ethanol (80 mL). The solution was diluted with 2M hydrochloric acid (1.8 mL) and water (20 mL). 20% Palladium hydroxide on carbon (0.63 g) was added and the mixture shaken on a Parr apparatus under 50 psi of hydrogen for 3.5 h. The catalyst was removed by filtration and the filtrate concentrated to a small volume. The solid present was redissolved by adding ethanol and the solution filtered. The filtrate was concentrated to a small volume once again to give a crystalline solid which was collected under suction, washed with cold ethanol and dried in vacuo to afford the title compound as colourless crystals (0.81 g, 91%); 1H NMR (500 MHz, CD3OD) δ 3.34–3.42 (1H, m), 3.80 (2H, d, J=7.6 Hz), 4.07 (2H, t, J=10 Hz), 4.14 (2H, t, J=10 Hz), 7.41–7.49 (2H, m), 7.80–7.84 (1H, m), 7.90–7.92 (1H, m); 19F NMR (471 MHz, CD3OD) δ −110.6; m/z (ES+) 230 ([M+H]+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:46][C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(F)c1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4cccc(F)c4)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1

Procedure:
A solution of the product from Example 43D and 3-Fluoro-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(3-fluoro-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (7 mg, 14%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 6.78 (m, 2 H) 6.93 (m, 4 H) 7.39 (m, 1 H) 7.55 (m, 1 H) 7.74 (m, 1 H) 7.85 (d, J=8.46 Hz, 1 H) 7.97 (dd, J=8.82, 2.21 Hz, 1 H) 8.13 (d, J=1.84 Hz, 1 H) 8.88 (s, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.42 (s, 1 H) 11.34 (s, 1 H); MS (ESI+) m/z 510 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[S:5][C:4]=1[NH2:12].[C:13]1([S:19]([Cl:22])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[ClH:22].[Br:2][C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[S:5][C:4]=1[NH:12][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1sc2cccnc2c1Br
Agent: Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1sc2cccnc2c1Br)c1ccccc1
Temperature: 50 °C
Yield: 35.7 %

Procedure:
To a solution of compound 145-H (0.46 g, 1.52 mmol) in pyridine (4.6 mL), cooled to 0° C., was added benzenesulfonyl chloride (0.206 mL, 1.60 mmol), and the reaction was heated to 50° C. for 72 h. Additional benzenesulfonyl chloride (0.412 mL, 3.20 mmol) was added and the reaction mixture was heated at 50° C. for an additional 16 h. The solvent was evaporated in vacuo, the residue dissolved in dichloromethane and washed with aqueous sodium bicarbonate. The aqueous layer was acidified with 1N HCl, extracted with dichloromethane, and the organic layer was evaporated in vacuo to afford a yellow solid (0.22 g, 36%) as a 1/3.5 mixture of the 3-bromo- and 3-chloro-substituted compounds, 145-Ia and 145-Ib, respectively. 1H-NMR (DMSO-d6): δ 7.1-7.2 (m, 1H), 7.4-7.6 (m, 3H), 7.8 (m, 2H), 8.1-8.2 (m, 1H), 8.25-8.35 (m, 1H); MS: m/z 465 and 509 (MH+).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[CH2:16][CH2:17][C@@:11]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:12]([OH:18])[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:30]Br.C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[CH2:16][CH2:17][C@@:11]1([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:12]([O:18][CH2:30][C:29]1[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=1)[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3CC[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 127 %

Procedure:
Sodium hydride (60% in oil, 90 mg, 2.25 mmol) was washed twice with THF and treated with a solution of (1R,2R,5R)-8-benzyl-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 53; 79 mg, 0.25 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (350 mg, 1.14 mmol), 18-crown-6 (110 mg, 0.41 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 24 hours, quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether) to give the title compound (165 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH:12]1[CH2:16][CH2:15][CH:14]=[CH:13]1.C(N(CC)CC)C>ClCCl>[N:12]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:11][CH:10]=2)=[O:9])[CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: C1=CNCC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.2 g (35 mmol) of 4-formylbenzoic acid was dissolved in 100 ml of dichloromethane. 2.0 g (29 mmol) of pyrroline, 5.9 g (35 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 6.1 ml (43 mmol) of triethylamine were added to the obtained solution, and they were stirred at room temperature for 5 hours. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the crude product was obtained.