Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.N1C=CN=C1.[CH2:11]([O:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=O)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].C(=O)([O-])O.[Na+]>CC(N(C)C)=O.C(OCC)(=O)C.O>[I:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:23](=[O:25])[CH2:22][NH:21][C:19]([O:18][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:20]
Reactant: Nc1ccccc1I
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)Nc1ccccc1I
Yield: 86.5 %

Procedure:
Phosphorus oxychloride (2.2 ml, 24 mmol), imidazole (2.7 g, 40 mmol), and N-benzyloxycarbonylglycine (5.0 g, 24 mmol) are added to dimethylacetamide (32 ml) under ice cooling and stirring. After stirring for 5 minutes, a solution of 2-iodoaniline (4.4 g, 20 mmol) in DMA (10 ml) is added dropwise. The reaction mixture is stirred at 50° C. for 3 hours. After allowing to cool, water and ethyl acetate are added to the reaction mixture, and a saturated aqueous solution of sodium hydrogencarbonate is added to make pH 9, and the aqueous phase is extracted twice with ethyl acetate. The organic layer is washed with a saturated saline, dried over anhydrous magnesium sulfate, and then concentrated. To the residue is added isopropylether (40 ml), and the precipitated solid is filtered off to obtain the objective compound (7.10 g). Yield 86%.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:12]3[CH:13]=[CH:14][C:15]([F:20])=[CH:16][C:17]=3[C:18](=O)[C:10]=2[CH:9]=[C:8]2[C:3]=1C(C)=CC(C)(C)[NH:7]2.CCCCCC.CC[O:32]C(C)=O>>[NH2:7][C:8]1[C:9](=[O:32])[C:10]2[C:11](=[C:2]([F:1])[CH:3]=1)[C:12]1[C:17](=[CH:16][C:15]([F:20])=[CH:14][CH:13]=1)[CH:18]=2
Reactant: CC1=CC(C)(C)Nc2cc3c(c(F)c21)-c1ccc(F)cc1C3=O
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: NC1=CC(F)=C2C(=Cc3cc(F)ccc32)C1=O

Procedure:
This compound was prepared according to General Method 3 (EXAMPLE 16) from Compound 132 (1.0 g, 4.6 mmol) to afford 5,8-difluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindeno[1,2-g]quinoline (structure 19 of Scheme VI, where R2, R5 =F, R3-4, R6 =H). Data for 5,8-difluoro-1,2-dihydro-2,2,4-trimethyl-10-oxoindeno[1,2-g]quinoline: Rf =0.49 (silca gel, hexane/EtOAc, 3:1), 1H NMR (400 MHz, acetone-d6) 7.50 (dd, J=8.1, 4.6, 1H), 7.27 (m, 2H), 6.73 (s, 1H), 6.03 (br s, 1H), 5.47 (s, 1H), 2.16 (dd, J=7.1, 1.5, 3H), 1.29 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:33][CH:34]([Cl:38])[C:35]([NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12)=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(O)C1=C(CSc2cnn[nH]2)CS[C@@H]2C(NC(=O)C(Cl)Cl)C(=O)N12
Temperature: -7.5 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
7-Amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.98 g) was suspended in methylene chloride (10 ml) and bis(trimethylsilyl)acetamide (2.53 g) was added to the suspension to give a solution. To the solution was added dropwise a solution of dichloroacetyl chloride (0.46 g) in methylene chloride (10 ml) at -30° C. The mixture was stirred at -10°0 to -15° C for 30 minutes and then concentrated under reduced pressure. To the residue was added ethyl acetate (50 ml) and water (30 ml) and the mixture was stirred and filtered. The ethyl acetate layer was separated from the filtrate and concentrated under reduced pressure to a half of volume. Water (30 ml) was added to the concentrated solution and the mixture was adjusted to pH 7.2 by adding aqueous sodium bicarbonate under cooling and stirring. The aqueous layer was separated from the mixture, adjusted to pH 6 with diluted hydrochloric acid, washed with ethyl acetate, adjusted to pH 2 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and treated with activated charcoal powder. Ethyl acetate was distilled off from the solution under reduced pressure. The residue was pulverized by treating with ether and precipitates were collected by filtration to give 7-dichloroacetamido-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.56 g). The solvent was distilled off from the mother liquid under reduced pressure and the residue was pulverized by treating with diisopropyl ether. Precipitates were collected by filtration to give the same product (0.14 g). Total yield was 0.70 g.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=2)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:20][CH:18]([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=1)[O:21][C:22]1[CH:23]=[N:24][C:25]([C:36]2[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=2)=[CH:26][CH:27]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(C)C)Oc2ccc(Cl)nc2)cc1
Product: CC(C)CCCC(Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 62 starting from 3-{4-[1-(6-chloro-pyridin-3-yloxy)-5-methyl-hexyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. MS: 527.2[M−H]−.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6]
Reactant: C=C1CC(=O)O1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(C)CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of 30 ml (0.38 mol) 2-(methylamino)ethanol in 300 ml tetrahydrofuran was added dropwise to a solution of 30 g of diketene (0.36 mol) in 300 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 41.46 g (0.26 mol, 73% yield) of a white solid.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[Cl:12][CH2:13][C:14](=[O:26])[C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]([OH:18])=O.[NH2:27][CH:28]1[C:40](=[O:41])[N:30]2[C:31]([C:37]([OH:39])=[O:38])=[C:32]([CH:35]=[CH2:36])[CH2:33][S:34][C@H:29]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[Cl:12][CH2:13][C:14](=[O:26])[C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:16]([NH:27][CH:28]1[C:40](=[O:41])[N:30]2[C:31]([C:37]([OH:39])=[O:38])=[C:32]([CH:35]=[CH2:36])[CH2:33][S:34][C@H:29]12)=[O:18]
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: COC(=O)CON=C(C(=O)O)C(=O)CCl
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Yield: 85 %

Procedure:
Vilsmeier reagent prepared from N,N-dimethylformamide (3.76 ml) and phosphorus oxychloride (4.46 ml) was suspended in dry tetrahydrofuran (50 ml). To the suspension was added 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (10.5 g), and the mixture was stirred under ice-cooling to prepare the activated acid solution. This solution was added at a time to a solution of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (10 g) and trimethylsilylacetamide (35 g) in ethyl acetate (110 ml) at -30° C. After the reaction mixture was stirred at -15° C. for an hour, the resultant solution was poured into water (100 ml) and then extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was triturated with diisopropyl ether to give 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (16.75 g).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24]C(=O)C2C=CC=CC=2)=[CH:19][C:18]=1[Cl:33])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>CO.O>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([Cl:33])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[Cl:23])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(COCCCCCOc1c(Cl)cc(OC(=O)c2ccccc2)cc1Cl)=NOC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(COCCCCCOc1c(Cl)cc(O)cc1Cl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.99 g of 5-(2,6-dichloro-4-(benzoyloxy)phenoxy)pentyloxyacetone O-tert-butyloxime dissolved in 7.5 ml of methanol is added a solution of 0.15 g of potassium hydroxide dissolved in 1.5 ml of water. After stirring at room temperature for 1 hour, the reaction mixture is acidified by the addition of diluted hydrochloric acid, and concentrated. Water is added to the residue, and the mixture is extracted twice with ethyl acetate. The ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-hydroxyphenoxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([O:28][CH2:29][C@@H:30]([NH2:39])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.C(OCC)(=O)C>[P:26]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])([O:28][CH2:29][C@@H:30]([NH:39][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C@@H:8]3[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]3)[N:4]=2)=[CH:17][C:18]=1[F:25])[C:31]1[CH:36]=[C:35]([I:37])[CH:34]=[C:33]([F:38])[CH:32]=1)=[O:27]
Reactant: CC(C)(C)OP(=O)(OC[C@@H](N)c1cc(F)cc(I)c1)OC(C)(C)C
Reactant: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OP(=O)(OC[C@@H](NC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F)c1cc(F)cc(I)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid (215 mg, 0.509 mmol) in NMP (Volume: 4 mL) was added (S)-2-amino-2-(3-fluoro-5-iodophenyl)ethyl di-tert-butyl phosphate (260 mg, 0.509 mmol), DIEA (0.534 mL, 3.06 mmol) and then HATU (290 mg, 0.764 mmol). The reaction mixture was stirred at room temperature for 1 hour, followed by LCMS. To the crude reaction was added 150 ml of ethyl acetate washed with saturated bicarbonate (2×), water (3×), saturated salt solution, dried sodium sulfate, filtered and dried to residue. The crude product was purified by silica gel chromatograph 24 g column (DCM loading) eluting with 0-80% (EtOAc with 10% MeOH)/heptane. The desired fractions were concentrated to constant mass to give 315 mg of desired product as free base. (77% yield). LCMS (m/z): 805.3 (MH+), 1.01 min.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12](C)[C:13](=O)OC(C)(C)C)=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([CH3:28])=[C:21]([CH:9]([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[O:2][CH3:1])[CH2:10][CH2:11][NH:12][CH3:13])[CH:26]=1
Reactant: COC(=O)NCCOC(CCN(C)C(=O)OC(C)(C)C)c1cc(Cl)ccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC(OCCNC(=O)OC)c1cc(Cl)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 143.8 %

Procedure:
tert-butyl 3-(2-(methoxycarbonyl)aminoethoxy)-3-(2-methyl-5-chlorophenyl)propyl(methyl)carbamate (110 mg) was dissolved in a solution of 20% (V/V) TFA/CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford methyl 2-(1-(5-chloro-2-methylphenyl)-3-(methylamino)propoxy)ethylcarbamate (120 mg, 100%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:17][C:16]3[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=3[C:9]=2[CH:10]=1)(=[O:4])=[O:3].[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([CH:30]=[CH:31][N:32]2[S:2]([C:5]2[CH:6]=[CH:7][C:8]3[O:17][C:16]4[CH2:15][CH2:14][N:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12][C:11]=4[C:9]=3[CH:10]=2)(=[O:4])=[O:3])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Reactant: Fc1ccc2cc[nH]c2c1
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)n4ccc5ccc(F)cc54)cc3c2C1
Yield: 55 %

Procedure:
The product of Example 41, step B was reacted with 6-fluoroindole following the procedure of Example 41, step C providing tert-butyl 8-(6-fluoro-1H-indol-1-ylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (63 mg, 55%) as a white foamy solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (s, 1H), 7.75 (dd, J=9.6, 2.1 Hz, 2H), 7.58 (d, J=4.0 Hz, 1H), 7.44 (m, 2H), 6.96 (dt, J=4.5, 2.5 Hz, 1H), 6.63 (d, J=4.1 Hz, 1H), 4.55 (br s, 2H), 3.81 (br s, 2H), 2.84 (br s, 2H), 1.51 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[CH:50]=[C:49]([NH2:51])[O:48][N:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:41])([CH3:40])[C:37]([NH:51][C:49]5[O:48][N:47]=[C:46]([CH3:45])[CH:50]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)on1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4cc(C)no4)c3)cc12
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 3-methylisoxazol-5-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (3.3 mg, 11%). 1H NMR (500 MHz, CD3OD) δ ppm 8.18-8.24 (1H, m), 7.93-8.00 (3H, m), 7.84-7.91 (2H, m), 7.65-7.74 (2H, m), 7.58 (1H, t, J=7.78 Hz), 7.23-7.31 (2H, m), 2.98 (3H, s), 2.24 (3H, s), 1.65 (6H, s). LC-MS retention time: 1.69 min; m/z (MH+): 555. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=12.09 min, purity=100%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=11.18 min, purity=99%.
Reaction SMILES: [C:1]1(=[O:14])[N:12]2[C:13]3[C:5](=[CH:6][CH2:7][CH2:8][C:9]=3[CH:10]=[CH:11]2)[CH2:4][NH:3][CH2:2]1>O>[C:1]1(=[O:14])[N:12]2[C:13]3[C:9]([CH:10]=[CH:11]2)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][NH:3][CH2:2]1
Reactant: O=C1CNCC2=CCCc3ccn1c32
Solvent: O
Product: O=C1CNCc2cccc3ccn1c23

Procedure:
This known compound was prepared from 3,4,6,7-tetrahydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-one (Example 41) according to the general procedure of Hester et al. and references cited therein (Hester et al., J. Med. Chem. 13, 827 (1970)): 1H NMR (DMSO-d6) δ 3.52-3.56 (m, 2H), 4.31-4.36 (m, 2H), 6.53 (d, 1H, J=3.0 Hz), 7.11 (t, 1H, J=6.0 Hz), 7.38 (d, 1H, J=3.0 Hz), 7.70 (d, 1H, J=6.0 Hz), 7.80 (d, 1H, J=6.0 Hz), 8.30 (bs, 1H). LRMS (M+) 186. Anal. (C11H10N2O.0.05 H2O) C, H, N.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.C(N(CC)CC)C>CC(O)C>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[NH:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CN)C1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2ncnc3ccc(C(F)(F)F)cc23)C1

Procedure:
A mixture of tert-butyl 3-(2-aminoacetamido)azetidine-1-carboxylate (1.073 g, 4.682 mmol) as prepared in the previous step and commercially available 4-chloro-6-(trifluoromethyl)quinazoline (990 mg, 4.256 mmol) were stirred in anhydrous iPrOH and triethylamine at 90° C. under argon for 1 hour. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0%-5% MeOH/EtOAc) to give a yellow solid after drying under high vacuum.
Reaction SMILES: [OH-].[K+].C(O)CO.[OH:7][C:8]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH2:40][CH2:41][O:42]C(=O)C)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1.Cl>O>[OH:7][C:8]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH2:40][CH2:41][OH:42])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1
Reactant: COC(=O)C(CCN1CCC(O)(c2ccccc2OCCOC(C)=O)CC1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
In a mixture of 4 mL of a 25% aqueous solution of potassium hydroxide and 5 mL of ethylene glycol was dissolved 350 mg (0.66 mmol) of methyl 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyrate. The resulting solution was stirred at 130° C. for 2 hours. Water was added to the reaction mixture, followed by neutralization with hydrochloric acid under ice cooling. The crystals thus precipitated were collected by filtration and dried, whereby 230 mg (yield: 73.4%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid was obtained.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH:73]OS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:72])=[N:14][C:15]2[N:16]([N:50]=[C:51]([CH:53]=[CH:54][CH2:55][C:56]3[CH:61]=[CH:60][C:59]([F:62])=[CH:58][C:57]=3[OH:73])[CH:52]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([O:32][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:31])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3B3OC(C)(C)C(C)(C)O3)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3ccc(F)cc3O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (450 mg, 0.449 mmol) in Acetone (6 mL) was added solution of oxone (276 mg, 0.449 mmol) in water (6 mL) and the resulting mixture was stirred at room temp for 1 h. Sat. sodium thiosulfate was then added and the mixture was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(4-fluoro-2-hydroxyphenyl)prop-1-en-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (370 mg, 0.414 mmol, 92% yield) as viscous oil. Product is a mixture of isomers LCMS (M+H)=893.4. Used as is in the next reaction without further purification.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24]>C1COCC1.CO.O>[CH3:4][O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.2 %

Procedure:
Lithium hydroxide monohydrate (2.29 g, 54.7 mmol) was added into a solution of methyl 2-(methoxymethyl)-2′-(trifluoromethyl)biphenyl-4-carboxylate (8.0 g, 27.3 mmol) in THF (100 mL), MeOH (30 mL) and water (30 mL). The resulting mixture was stirred at RT for 12 hours, and then the reaction mixture was concentrated under vacuum. The remaining aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. Then the organic layer was washed with water and brine, and then dried (Na2SO4) and concentrated under vacuum. The resulting solid was suspended in Et2O (30 mL), filtered and dried under vacuum to afford of the title compound as a pale yellow solid (6.2 g, 74%). LC/MS (Method B): 309.0 (M−H)−. 1H NMR (DMSO-d6, 400 MHz) δ 13.08 (1H, s), 8.06 (1H, s), 7.87 (2H, m), 7.73 (1H, m), 7.65 (1H, m), 7.35 (1H, d, J=7.5 Hz), 7.27 (1H, d, J=7.9 Hz), 4.11-4.03 (2H, m), 3.15 (3H, s).