Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH2:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[C:11]3[S:12][CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[N:15]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH2:65].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:60][O:61][C:62](=[O:67])[C@H:63]([OH:66])[CH2:64][NH:65][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([CH2:27][N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)[C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=3)[N:15]=2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Reactant: COC(=O)[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2ccc3c(c2)CCC3)c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-({Indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoic acid (0.44 g, 0.86 mmol) was dissolved in DMF (10 mL) and 1-hydroxybenzotriazole (0.18 g, 1.29 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.25 g, 1.29 mmol) were added and the resulting mixture was stirred at room temperature for 1.5 hours. 3-Amino-2(R)-hydroxypropionic acid methyl ester hydrochloride, (R-isoserine methyl ester hydrochloride), prepared as described in WO 02/00612, (0.16 g, 1.03 mmol) and DIPEA (225 μL, 1.29 mmol) were added and the resulting mixture was stirred at room temperature for 16 hours. Ethyl acetate (100 mL) was added and the mixture was washed with water (2×80 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The residue (0.35 g) was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate and heptane (1:1). This afforded 0.10 g (19%) of 2(R)-Hydroxy-3-[4-({indan-5-yl-[4-(4-trifluoromethoxyphenyl)thiazol-2-yl]amino}methyl)benzoylamino]propionic acid methyl ester.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[OH:25][CH2:26][CH2:27][N:28]([CH2:38][CH2:39][OH:40])[S:29]([C:32]1[S:33][C:34]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (169 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.53) (165 mg, 0.5 mmol) according to general procedure II. Obtained as a light brown solid (78 mg, 27%). MS (ISP) 587.1 [(M+H)+]; mp 122° C.
Reaction SMILES: C(OC([N:8]1[CH2:23][CH2:22][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OCC)(=O)C>[ClH:24].[C:16]1([C:13]2[N:14]=[CH:15][C:10]3[CH2:9][NH:8][CH2:23][CH2:22][C:11]=3[N:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(-c3ccccc3)ncc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncc3c(n2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 2-phenyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester (prepared according to the method of Example 101, Step C, 304 mg, 0.98 mmol) in ethyl acetate (2 mL) was added hydrogen chloride (2.5 M in ethyl acetate, 3.9 mL, 9.76 mmol). This mixture was stirred at room temperature for 16 h and concentrated to give 256 mg (>100%) of the title compound of Example 101, Step D as a pale yellow solid. 1H NMR (CD3OD, 400 MHz) δ8.75 (s, 1H), 8.42-8.38 (c, 2H), 7.51-7.45 (c, 3H), 4.48 (s, 2H), 3.68 (t, 2H) 3.35-3.25 (buried, 2H); MS (APCI) 212 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH2:4].[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21].C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O.C(OCC)(=O)C.O1CCCC1.N1C=CC=CC=1>[CH3:1][C:2]1[CH:8]=[C:7]([C:9]([OH:18])([C:10]([F:12])([F:13])[F:11])[C:14]([F:15])([F:16])[F:17])[CH:6]=[C:5]([CH3:19])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 98.7 %

Procedure:
At room temperature, 5.0 g of 2,6-dimethyl-4-[1-hydroxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline, 3.9 g of 3-nitrobenzoyl chloride and 2.1 g of pyridine were introduced to 50 ml of tetrahydrofuran in a reaction vessel, and the resulting mixture was stirred at room temperature. After disappearance of the starting raw material was confirmed by means of TLC, to the reaction solution was added saturated baking soda solution and stirred for a while. Subsequently, ethyl acetate and water were added to the reaction solution for solution separation. Anhydrous magnesium sulfate was added to a separated organic layer, the organic layer was dried and filtered off. The filtrate was evaporated to be dried and the resulting solid was pulverized to obtain 7.5 g of the desired product (Yield: 95%) in the form of powder.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8]C)=[O:7])[CH2:3][CH2:2]1.CO[CH:13](OC)[N:14](C)C.O.Cl.NO>CO>[CH:1]1([C:4]2[O:10][N:14]=[CH:13][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: O
Product: O=C(O)c1cnoc1C1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Methyl 3-cyclopropyl-3-oxopropanoate (0.28 g, 2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.24 g, 2 mmol) was mixed and heated for 20 h at 60° C. The bright yellow oil was dissolved in methanol (2 mL) and H2O (1 mL) and hydroxylamine hydrochloride (0.14 g, 2 mmol) was added, resulting in a pH of ca 5. The reaction was heated for 90 min at 60° C. The solvents were evaporated and the residue refluxed in acetic acid: conc. HCl (3+3 mL) for 4 h. The mixture was stored at room temperature for 2 days and the solid was filtered off and dried in vacuum to yield the title compound as a grey solid. This compound is also commercially available. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.18-1.28 (m, 2 H) 1.28-1.35 (m, 2 H) 2.78-2.90 (m, 1 H) 8.45 (s, 1 H)
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][C:17]([CH3:20])(C)C)=[O:15])[C:3]1=[O:21].O.[C:23]1(C)[CH:28]=[CH:27]C(S(O)(=O)=O)=[CH:25][CH:24]=1.C(O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([CH2:13][C:14]([O:16][CH2:17][C:20]2[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=2)=[O:15])[C:3]1=[O:21]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCc1ccccc1
Solvent: O
Product: NC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 4 h
Yield: 69.9 %

Procedure:
10.5 g of tert-butyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (see Example 1I) for preparation), 8.25 g of p-toluenesulfonic acid hydrate and 20.1 ml of benzyl alcohol were added to 174 ml of toluene. The reaction mixture was boiled with a water trap for 4 hours, during which a precipitate which originally separated out slowly dissolved. The toluene was then stripped off under reduced pressure, and the remaining residue was stirred with methyl tert-butyl ether and then filtered out. The resulting solid residue was dissolved in dichloromethane, and the solution was made alkaline by adding aqueous sodium carbonate solution while cooling in ice. The dichloromethane phase was then separated, washed with water, dried over sodium sulfate and evaporated. The resulting crude product was recrystallized from methyl tert-butyl ether for purification. 8.2 g of benzyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained with a melting point of 105° to 107° C.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C([Sn](=O)CCCC)CCC.C([C@@]1(O)[C@H](OCCCC)[C@@H](C(=[SnH2])O)O[C@H]1N1C=CC(=O)NC1=O)CCC.I[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>>[CH2:55]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]1=[O:12])[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCI
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: CCCCO[C@@H]1[C@@H](C(O)=[SnH2])O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]1(O)CCCC
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
As per the procedure of Example 49, uridine (22.5 g) was treated with dibutyl tin oxide (22.5 g, 1 eq). The resulting 2',3'-O-dibutylstannyleneuridine was treated with iodononane (11 ml, 1.3 eq.) at 130-140° C. as per Example 50 to give the 2' and 3' isomers (11.2 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[N:7]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([C@H:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][C:40]=1[CH3:47]>>[NH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:43][C:42]1[CH:45]=[CH:46][C:39]([F:38])=[C:40]([CH3:47])[CH:41]=1)[C@@H:12]([C:8]1[N:7]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:6](=[O:37])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][CH3:14]
Reactant: Cc1cc(C=O)ccc1F
Reactant: CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Product: CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccc(F)c(C)c1

Procedure:
This compound was synthesized as described in general procedure C except 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-propylamino]-propyl}-isoindole-1,3-dione was used instead of (R)-2-(3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propyl)isoindoline-1,3-dione and 4-fluoro-3-methyl benzaldehyde was used instead of 4-methyl benzaldehyde. LCMS: m/e 508.04 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][N:46]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)[CH:47]=2)O1.C(=O)(O)[O-]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:43]3[CH:44]=[N:45][N:46]([CH2:48][CH2:49][N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH:47]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cnn(CCN3CCOCC3)c2)OC1(C)C
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3cnn(CCN5CCOCC5)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 1F) (200 mg, 0.318 mmol) and 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine (127 mg, 0.413 mmol) in N,N-dimethylformamide (0.79 mL) was added saturated aqueous bicarbonate solution (0.79 mL) followed by bis(triphenylphosphine)palladium dichloride (15.60 mg, 0.022 mmol). The mixture was heated to 70° C. for 4 hours and was then quenched by the addition of water and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel, eluting with a gradient of 20% ethyl acetate in hexane to 100% ethyl acetate with 3% methanol, to afford the title compound. MS ESI(+) m/z 683.52 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=4)=[CH:16][C:9]=23)[C:5]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:31])=[CH:25][CH:24]=2)=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:60][N:61]([CH3:66])[CH2:62][C:63](O)=[O:64]>CN(C)C=O.C(OCC)(=O)C>[CH3:60][N:61]([CH3:66])[CH2:62][C:63]([N:20]1[CH2:19][CH:18]=[C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[C:5]([C:23]5[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33]6[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=6)=[O:31])=[CH:25][CH:24]=5)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)=[C:9]3[CH:16]=2)[CH2:22][CH2:21]1)=[O:64]
Reactant: CCn1cc(-c2ccnc3[nH]c(C4=CCNCC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Reactant: CN(C)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCn1cc(-c2ccnc3[nH]c(C4=CCN(C(=O)CN(C)C)CC4)cc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N-(4-{1-ethyl-4-[2-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-N′-phenylurea (0.23 mmol) was in N,N-dimethylformamide (3.0 mL) was added EDC (0.39 mmol), HOBt (0.39 mmol), triethylamine (1.38 mmol) followed by N,N dimethylglycine (0.39 mmol). The reaction stirred at room temp for 16 h. The reaction was poured into ethyl acetate and washed saturated sodium bicarbonate (2×10 mL). The organic layer was evaporated and purification of the residue by Gilson reverse phase HPLC provided the title product. ESMS [M+H]+: 589.4
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]3[N:23]=[N:24][NH:25][N:12]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.6 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (200 mg, 0.565 mmol) in DMF (3 mL), follow by the addition of NaN3 (48 mmol, 0.738 mmol) and NH4Cl (39 mg, 0.729 mmol). The reaction mixture is stirred at 110° C. for 48 hours. The reaction mixture is diluted with EtOAc/water. The organic layer is separated, washed with water then brine, dried with Na2SO4, filtered and concentrated to afford 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (190 mg, 85%) as a solid product. LCMS (ESMS): m/z 397.49, 399.40 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH:10]([CH:19]([C:24]([O:26][CH3:27])=[O:25])[C:20](OC)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C[O-].[Na+].Cl>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:20](=[O:21])[CH:19]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH2:9][C:3]=2[CH:4]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(Cl)ccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of [2-(2-amino-5-chlorophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (23.2 g, 59.2 mmole) in methanol (200 ml) was added a 25% solution of sodium methoxide in methanol (16 ml, 69.97 mmole). The solution was refluxed for 3 hours under argon. The reaction was cooled to room temperature and treated with 200 ml 1N hydrochloric acid. A white precipitate was filtered and washed with water, methanol, and dried in vacuo to yield 19.5 g of the title compound, melting point 189°-190.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH:17]([O:24][CH3:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH:17]([O:24][CH3:25])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: COC(CC(C)Nc1c(C)noc1-c1ccc(Br)cc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CC(OC)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(3-methoxy-1-methyl-3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([Cl:14])[N:20]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g, 4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10 equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol, 1.40 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated aqueous NaCl (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1.0 g, white solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6 Hz, 3H); MS m/z 334.0 (M+H)+; Rt-1.10 min.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[Cl:35]C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.C(Cl)Cl>[C:1]([O:4][C@@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C:19]2=[O:23])[C@H:15]2[C@H:6]1[C@@H:7]1[C:12]([CH2:13][C@H:14]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][Cl:35])=[CH:11][C:10](=[O:34])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCO)CC3=CC(=O)CC[C@@H]3[C@H]21
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)O[C@@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2[C@H](CCCCCCCCCCl)CC3=CC(=O)CC[C@@H]3[C@H]21
Reaction time: 5 h

Procedure:
15.8 g of 11α-acetoxy-7α-(9-hydroxynonyl)-estr-4-ene-3,17-dione is reacted in 65 ml of acetonitrile with 184 ml of tetrachloromethane and 17.9 g of triphenylphosphine at room temperature. After 5 hours, it is diluted with methylene chloride, washed neutral with saturated sodium bicarbonate solution and water and dried. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient. Yield: 7.8 g of 11α-acetoxy-7α-(9-chlorononyl)-estr-4-ene-3,17-dione with a melting point of 113-115° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1.[CH2:21]([OH:24])[CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][O:24][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:20])([F:19])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:23][CH2:22][CH2:21][OH:24])=[CH:14][CH:13]=2)([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: Fc1ccc(C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Product: OCCOc1ccc(C(F)(F)C(F)(F)c2ccc(OCCO)cc2)cc1
Temperature: 150 °C
Reaction time: 7 h

Procedure:
700 ml of ethylene glycol and 65 g of 1,2-bis(4-fluorophenyl)-1,1,2,2-tetrafluoroethane* are heated to 110° C. in a stirred flask. 57 g of potassium tert.-butylate are added in portions and the mixture is then stirred at 150° C. for 7 hours. The mixture is cooled, poured onto 4 liters of ice-water and mixed thoroughly with a homogenizer (Ultraturax). The crystals which have precipitated are filtered-off with suction, stirred again with 2 liters of water filtered-off with suction again, dried and recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([OH:24])=O)[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][NH:32]C(=O)OC(C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>CS(C)=O.C(N(CC)CC)C>[NH2:32][CH2:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][N:25]1[C:22]([C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=3[N:10]=2)=[O:6])=[CH:3][C:2]=1[Cl:1])=[O:24]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCCCN1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, tert-butyl piperidin-2-ylmethylcarbamate, TBTU, and triethylamine in DMSO at ambient temperature followed by Boc cleaving with trifluoroacetic acid analogously to Example 17.