Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[CH:34]=[CH:35][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)=[CH:30][CH:29]=2)[C:32]1=[O:36])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(Cn2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ccn(-c2ccc(Cn3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 1-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone in the same manner as in Working Example 11 to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-2(1H,3H)-imidazolone (Compound 28).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13](Br)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].B[C:27]1[CH:31]=[CH:30][N:29]([Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:28]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([C:27]3[CH:31]=[CH:30][N:29]([Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[CH:28]=3)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Bc1ccn([Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(Cc2ccccc2)c2cccc(Br)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cccc3c2n(C(=O)OC(C)(C)C)c(=O)n3Cc2ccccc2)c1
Temperature: 85 °C
Yield: 77.1 %

Procedure:
To 10 mL of a 9:1 mixture of dimethoxyethane/water was added 3-benzyl-7-bromo-2-oxo-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester (0.719 g, 1.783 mmol), 3-boranyl-1-triisopropylsilanyl-1H-pyrrole (0.476 g, 1.783 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (69.7 mg, 0.089 mmol), and cesium carbonate (0.697 g, 2.139 mmol.) The resulting suspension was vacuum-purged with argon and heated to 85° C. for 1 hour. The reaction mixture was added to 100 mL of 1:1 water/ethyl acetate and the organic layer was separated. The combined organic fractions were washed with 100 mL each of water and brine and dried over sodium sulfate. Concentration in vacuo gave a crude solid which was purified by flash chromatography (0 to 10% gradient ethyl acetate in hexanes) to give 0.750 g of 3-benzyl-2-oxo-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-2,3-dihydro-benzoimidazole-1-carboxylic acid tert-butyl ester as a white solid. MS: 446 (M−BOC+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15][CH3:16])=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1.[OH-:25].[NH4+]>C(O)(=O)C.OO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([S:15]([CH3:16])=[O:25])=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:6]=2[CH:24]=1
Reactant: [OH-]
Reactant: CSc1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Product: CS(=O)c1ncc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 8 h

Procedure:
A solution of 450 mg (1.25 mmol) of the end product of Example 25 in 10 ml of acetic acid and 1 ml of 30% hydrogen peroxide was allowed to stand at room temperature overnight. The solution was treated with ice and ammonium hydroxide; the resulting solid was collected, washed with water, dissolved in methylene chloride, treated with anhydrous sodium sulfate and charcoal, filtered and evaporated in vacuo to a white foam, mp 95°-110°: Ir (KBr) 1610, 1480 and 1047 cm-1 ; nmr (CDCl3) 2.95 (s, 3H), 4.15 (d, J=13Hz, 1H), 5.25 (d, J=13Hz, 1H), 6.95-8.40 (m, aromatic, 8H); uv λ max 219 nm (ε=37500), infl. 243 (20000); sh. 265 (13700), infl. 305 (1200); mass spectrum m/e 373 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH2:16]([NH:18][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]([OH:15])=[O:14])=[CH:5]2)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Yield: 93 %

Procedure:
A mixture of 4.08 g (20 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 2.37 ml (30 mmol) of ethyl isocyanate, 2.8 ml (20 mmol) of triethylamine and 50 ml of dimethylformamide is stirred with ice bath cooling for 4.5 hrs. The reaction solution is evaporated to dryness and is treated with 1 N hydrochloric acid and ethanol to yield 5.12 g of 6-[[(ethylamino)carbonyl]amino]-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:12]2[CH2:13][CH2:14][CH:15]([CH3:16])[C:11]=2[NH:10][N:9]=1)=[O:7])C>CO>[CH3:16][CH:15]1[C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=2[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1n[nH]c2c1CCC2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1CCc2c(C(=O)O)n[nH]c21
Yield: 73.6 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 5.02 mmol) was added to a stirring, room temperature solution of 5 (0.1949 g, 1.00 mmol) in MeOH (12.5 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by TLC (0.5 h). The reaction was concentrated and then dissolved in 2 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.1223 g (73.3%) of 6. 1H (CD3OD, 400 MHz): δ 3.18-3.07 (1H, m), 2.84-2.62 (3H, m), 2.08-1.96 (1H, m), 1.25 (3H, d, J=6.8 Hz) ppm. 13C (CD3OD, δ 164.49, 163.43, 131.67, 129.41, 40.87, 33.40, 23.61, 19.73 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 19.73; CH2 carbons: 40.87, 23.61; CH carbons: 33.40 ppm. HPLC: 7.006 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.O=S(Cl)[Cl:17]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([Cl:17])=[O:14]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCCCCCCCCBr

Procedure:
A solution of 11-bromoundecanoic acid (10.00 g, 37.7 mmol) dissolved in CH2Cl2 (30 mL) was slowly added to a solution of SOCl2 (7.0 mL, 94.0 mmol) in CH2Cl2 (25 mL). The mixture was refluxed for 5 h, then concentrated in vacuo to give 11-bromoundecanoyl chloride, which was used without further purification: 1H NMR (CDCl3) δ1.26 (bs, (CH2)5, 10H), 1.34 (m, CH2CH2CH2Br, 2H), 1.67 (m, CH2CH2COCl, 2H), 1.81 (m, CH2CH2Br, 2H), 2.85 (t, CH2COCl, J=7.2 Hz, 2H), 3.36 (t, CH2Br, J=6.8 Hz, 2H); 13C NMR (CDCl3) δ24.89 (CH2CH2COCl), 27.95 (CH2CH2CH2Br), 28.21, 28.52, 28.84, 29.02, and 29.12 ((CH2)5) 32.64 (CH2CH2Br), 33.80 (CH2Br), 46.92 (CH2COCl), 173.47 (COCl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH:20]1([Mg]Br)[CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:20]2[CH2:22][CH2:21]2)=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Reactant: Br[Mg]C1CC1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1C1CC1
Temperature: -20 °C
Yield: 211.4 %

Procedure:
To a solution 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (7.0 g, 24.6 mmol) in tetrahydrofuran-N-methyl-2-pyrrolidone (2:3) (250 ml) is added iron(III) acetylacetonate (1.74 g, 4.92 mmol) and the mixture is cooled to −20° C. At this temperature, a solution of cyclopropylmagnesium bromide (0.7 M in tetrahydrofuran) (105 ml, 73.8 mmol) is slowly added and the mixture is warmed to 0° C. within 30 min. After completion of the reaction, 10% aqueous ammonium chloride is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with water and brine, dried over magnesium sulphate and evaporated to dryness. The reaction is repeated once and the combined crude products are purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (15.1 g).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH2:9]([O:12][CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49](O)=[O:50])=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1)=[O:16])[C:10]#[CH:11].C(Cl)CCl>C(Cl)Cl>[CH2:9]([O:12][CH2:13][CH2:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:53]=[CH:52][C:25]([C:26]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][C:49]([O:1][N:2]3[C:6](=[O:7])[CH2:5][CH2:4][C:3]3=[O:8])=[O:50])=[CH:32][CH:33]=2)=[O:27])=[CH:24][CH:23]=1)=[O:16])[C:10]#[CH:11]
Reactant: O=C1CCC(=O)N1O
Reactant: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)O)cc2)cc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C#CCOCCC(=O)NCCCOc1ccc(C(=O)c2ccc(NCCOCCOCCOCCOCCC(=O)ON3C(=O)CCC3=O)cc2)cc1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
N-hydroxysuccinimide (252 mg, 2.30 mmol) was added to a solution of 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oic acid (1.25 g, 1.98 mmol) in anhydrous DCM (10 ml) was added followed by EDC (505 mg, 2.64 mmol). The reaction was stirred at r.t. for 2-3 hs. Upon completion, reaction was concentrated under reduced pressure and purified by silica gel chromatography (DCM to DCM:iPrOH gradient) to provide 1.16 g (1.63 mmol, 80% yield) of 2,5-dioxopyrrolidin-1-yl 1-((4-(4-(3-(3-(prop-2-yn-1-yloxy)propanamido)propoxy)benzoyl)phenyl)amino)-3,6,9,12-tetraoxapentadecan-15-oate as slightly yellow oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][C:4](O)=[O:5].[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[C:34]([Cl:40])[CH:33]=2)[C:28]([F:31])([F:30])[F:29])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:13].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:9][C:10]1[CH:24]=[C:23](/[CH:25]=[CH:26]/[CH:27]([C:32]2[CH:33]=[C:34]([Cl:40])[C:35]([Cl:39])=[C:36]([Cl:38])[CH:37]=2)[C:28]([F:31])([F:29])[F:30])[CH:22]=[CH:21][C:11]=1[C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:4](=[O:5])[CH2:3][C:2]([F:8])([F:7])[F:1])[CH2:17][CH2:16]1)=[O:13]
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Reactant: O=C(O)CC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(C(=O)CC(F)(F)F)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,3,3-trifluoropropanoic acid (0.02 g, 0.16 mmol) in DCM (10.0 mL), (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol), PYBOP (0.09 g, 0.17 mmol), and DIPEA (0.06 g, 0.48 mmol) were added at RT. The reaction mixture was stirred at RT for 5 h. The reaction mixture was diluted with DCM. The combined DCM layer was washed with 3N HCl and saturated NaHCO3 solution, the separated DCM layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; eluting with 2% methanol in DCM) to afford the title compound as an off white gummy material (0.035 g, 29.%).
Reaction SMILES: [C:1]1([CH2:6][OH:7])([CH2:4][OH:5])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10]>C(Cl)Cl>[CH3:8][S:9]([O:5][CH2:4][C:1]1([CH2:6][OH:7])[CH2:3][CH2:2]1)(=[O:11])=[O:10]
Reactant: OCC1(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopropane-1,1-diyldimethanol (0.1 g, 0.98 mmol) in DCM (5 mL) was added TEA (0.15 g, 1.44 mmol). Methanesulfonyl chloride (0.11 g, 0.98 mmol) was added dropwise at 0° C. The reaction was stirred at room temperature for 2 h. The mixture was partitioned between DCM and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([OH:27])=O)[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.S(Cl)([Cl:30])=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([Cl:30])=[O:27])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C2Cc3c(C(=O)O)cc(OC)cc3C3CCCCC23)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2Cc3c(C(=O)Cl)cc(OC)cc3C3CCCCC23)cc1

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carboxylic acid (0.12 g, 0.33 mmol) and thionyl chloride (4 ml) and heat at 60° C. for 2 hours. Remove thionyl chloride in vacuo at 40° C. Take the residue into ethyl acetate and wash with sodium bicarbonate solution 1×, followed by water. Dry the organic layer over anhydrous sodium sulfate and remove solvent in vacuo at 40° C. to yield preparation 120 (0.133 g, 100%). 1H NMR (CDCl3): 7.62 (s, 1H), 7.3 (m, 3H), 6.93 (d, J=8.4, 2H), 3.92 (s, 3H), 3.85 (s, 3H), 3.3(m, 2H), 3.1 (m, 2H), 3.05 (m, 1H), 2.5 (m, 1H), 2.1 (m, 1H), 1.8 (m, 1H), 1.5 (m, 1H), 1.4-0.8 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2([OH:21])[CH2:20][N:17]([CH:16]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Product: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chlorophenylmagnesium bromide (9.1 mL, 10 M in diethyl ether) in diethyl ether (80 mL) at −78° C. under an argon atmosphere was added compound 3 (1.8 g, 7.6 mmol) in diethyl ether (50 mL) dropwise over 20 minutes. The reaction mixture was stirred at −78° C. for 2 hours, then slowly warmed to room temperature with stirring over 18 hours. The reaction mixture was then partitioned between aqueous ammonium acetate solution (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (3×50 mL) and the combined organic extracts were washed (water, brine), dried (Na2SO4), filtered and concentrated in vacuo to give the crude product as a pale yellow viscous oil in quantitative yield. A sample purified for analysis by column chromatography on silica gel using 15-30% ethyl acetate-hexane as eluent and subsequent crystallisation from bexane gave 3-(4-chorophenyl)-1-(diphenyhnethyl)-3-azetidinol (4), m.p. 108° C. Found: C, 75.42; H, 5.79; N, 3.98. C22H20CINO requires C, 75.53; H, 5.76; N, 4.00%.
Reaction SMILES: [CH3:1][O:2][NH2:3].Cl.[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:21])[S:11](=[O:20])(=[O:19])[C:12]([CH3:18])([CH3:17])[C:13](=O)[C:14]=2[N:15]=1>N1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH3:21])[S:11](=[O:19])(=[O:20])[C:12]([CH3:18])([CH3:17])[C:13](=[N:3][O:2][CH3:1])[C:14]=2[N:15]=1
Reactant: CN1c2ccc(Br)nc2C(=O)C(C)(C)S1(=O)=O
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1c2nc(Br)ccc2N(C)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of MeONH2.HCl (272 mg, 3.26 mmol) in pyridine (5 ml) was added 6-bromo-1,3,3-trimethyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one (130 mg, 0.41 mmol) and stirring was continued for 2 days at 100° C. The mixture was cooled to ambient temperature then concentrated under reduced pressure followed by addition of water and ethyl acetate then the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded 6-bromo-N-methoxy-1,3,3-trimethyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-imine as a yellow solid as a 5/1 mixture of oxime isomers.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:41])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:22]=[C:23]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=4)[C:24]4[N:29]=[CH:28][S:27][C:25]=4[N:26]=3)[CH:16]=2)=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][O:39][C:33]1[CH:32]=[C:31]([NH:30][C:23]2[C:24]3[N:29]=[CH:28][S:27][C:25]=3[N:26]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:42])=[O:5])=[CH:8][CH:9]=3)=[O:41])[N:22]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH3:38]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)c3)nc3scnc23)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(C(=O)O)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
tert-Butyl-4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoate (45 mg, 0.077 mmol) in 10 mL of DCM was treated with TFA (2 mL) dropwise. The resulting yellow solution was stirred at ambient temperature overnight. The excess of solvent was removed under reduced pressure, the residue was triturated with n-hexane decanted, and dried to give 4-(3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamido)benzoic acid (27 mg, 66.4%). 1H NMR (300 MHz, DMSO): δ 12.80 (brs, 1H), 10.76 (s, 1H), 10.19 (s, 1H), 9.41 (s, 1H), 8.96 (s, 1H), 8.62 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=7.8 Hz), 7.97 (s, 4H), 7.84 (s, 1H), 7.71 (t, 1H, J=7.7 Hz), 7.54 (dd, 1H, J1=8.7 Hz, J2=2.1 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.81 (s, 3H), 3.74 (s, 3H). LC-MS: 528 [M+H]+, tR=1.54 min. HPLC: 96.02% at 214 nm, 95.94% at 254 nm, tR=6.62 min.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.ClC(Cl)C.Cl[Si](C)(C)C>>[F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[N:10]=[C:8]([OH:9])[C:7]2[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1
Reactant: NC(=O)c1ccccc1NC(=O)C(F)(F)c1ccc(F)cn1
Agent: C[Si](C)(C)Cl
Solvent: CC(Cl)Cl
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2ccccc12
Temperature: 85 °C
Yield: 91.8 %

Procedure:
To 2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)benzamide (580 mg, 1.87 mmol) were added dichloroethane (15 mL) and TEA (11 mL, 75 mmol) followed by chlorotrimethylsilane (3.56 mL, 28 mmol) and the mixture was heated at 85° C. for 2-3 h. The mixture was concentrated to dryness and the residue was partitioned between saturated aq ammonium chloride and EtOAc. The organic layer was concentrated and the residue was purified by silica gel chromotography eluting with 0-10% MeOH/DCM to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol as a solid (500 mg, 91%). LC-MS (ESI) m/z 292 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: Oc1cccc(F)c1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(F)c4)nc3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) and 3-fluorophenol in a similar manner to that described for D55 in Description 55, yielding the title compound as a pale yellow oil (0.057 g). MS (ES): MH+ 535.3.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1>O1CCCC1>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]2=[O:27])=[O:37])=[CH:31][CH:30]=1
Reactant: CCN(CC)C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-diethylaminocarbonylmethyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 284°-285° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21](O)=[O:22])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(Cl)CCl.[NH2:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])=[CH:42][CH:41]=1>C(Cl)Cl.CN(C=O)C>[CH2:50]([NH:49][C:47]([NH:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][NH:38][C:21](=[O:22])[CH2:20][N:11]2[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:24])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]2=[O:19])=[CH:45][CH:44]=1)=[O:48])[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Reactant: NCc1ccc(NC(=O)NCc2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCc2ccc(NC(=O)NCc3ccccc3)cc2)C(=O)c2ccccc21
Reaction time: 1 h

Procedure:
130 mg (0.39 mmol) of the acid 3 are dissolved in 30 ml of CH2Cl2 and 0.07 ml of HUnig base and 77 mg of EDC (0.4 mmol) are added at 0° C. After 1 h, 100 mg of amine 5 dissolved in 10 ml of DMF are added dropwise and the mixture is stirred for a further 1 h. It is stirred at room temp. for 16 h, the solution is then concentrated, the residue is taken up in CH2Cl2/water and the mixture is washed with 1% citric acid, 5% NaHCO3 solution and water. The organic phase is dried and concentrated (92 mg).