Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C:22]2[C@:17]([CH3:24])([CH:18]=[CH:19][C:20](=[O:23])[CH:21]=2)[C@@H:16]2[C@H:4]([C@H:5]3[C@:13]([CH3:26])([CH2:14][C@@H:15]2[OH:25])[C@@H:8]([C:9](=[O:12])[CH2:10][OH:11])[C@H:7]([CH3:27])[CH2:6]3)[CH2:3]1.[C:28]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29]1.Cl>N1C=CC=CC=1>[C:28]([O:11][CH2:10][C:9](=[O:12])[C@@H:8]1[C@:13]2([CH3:26])[C@H:5]([C@H:4]3[C@H:16]([C@@H:15]([OH:25])[CH2:14]2)[C@:17]2([CH3:24])[C:22](=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]2)[C@@H:2]([F:1])[CH2:3]3)[CH2:6][C@H:7]1[CH3:27])(=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)COC(=O)CCC(=O)O
Temperature: 20 °C

Procedure:
Five grams of 6α-fluoro-11β,21 -dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione is refluxed in 25 ml. of pyridine with 5 g. of succinic acid anhydride for 2 hours. After cooling to 20°C., the solution is stirred into ice water, acidified with hydrochloric acid, and the thus-precipitated product is vacuumfiltered, washed with water, and dried. By recrystallization from ethyl acetate, 4.85 g. of (6α-fluoro-11β-hydroxy-3,20-dioxo-16α-methyl-1,4-pregnadien-21-yl) hydrogen succinate is obtained, m.p. 212°-214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(F)c(Cl)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(3-chloro-4-fluorophenyl)-boronic acid (CAN 144432-85-9) as starting materials; LC-MS (UV peak area/ESI) 98.0%, 424.0483 (M-H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3([OH:32])[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3([OH:32])[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[C:11]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2oc(-c3ccc(F)cc3)nc2-c2ccncc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2oc(-c3ccc(F)cc3)nc2-c2ccncc2)CCNCC1

Procedure:
tert-Butyl 4-[2-(4-fluorophenyl)-4-(pyridin-4-yl)-1,3-oxazol-5-yl]-4-hydroxypiperidine-1-carboxylate (60 mg, 0.14 mmol) was stirred in 4:1 DCM/TFA (5 ml) at room temperature for 3 h. Then the volatiles were removed under vacuum, and the resulting residue was purified by reverse phase HPLC (0.05% TFA-water-acetonitrile) to give the title compound. LC-MS m/e 340.15 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.N1C=CC=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][C:21]=1[S:30]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)(=[O:11])=[O:10])(=[O:32])=[O:31]
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of N-(2-amino-phenyl)-4-chlorobenzenesulfonamide (1.0 mmol, prepared as in Example 11) in DCM (2 mL) and pyridine (2 mL), 2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 419 mg of 2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylbenzenesulfonamide. LC: Tr 1.25 min; MS: 525.9 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[N:17]=[C:16]([C:18]([N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:30]=3[CH2:37][OH:38])[CH:14]=2)[N:9]=1.CO>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:1][N:2]([CH3:6])[C:3](=[O:4])[O:38][CH2:37][C:30]1[CH:31]=[C:32]([F:36])[C:33]([F:35])=[CH:34][C:29]=1[C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH2:7])[N:17]=[C:16]2[C:18]([N:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28]1)=[O:19]
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)C(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
20 μl of dimethylcarbamoyl chloride are added to a solution of 100 mg of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone and 2 mg of 4-(dimethylamino)pyridine (DMAP) in 5 ml of dimethylformamide (DMF), and the mixture is heated at 80° C. for 18 h. After 18 h, 10 ml of methanol are added, the mixture is evaporated to dryness in vacuo and purified by normal-phase chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][S:23][C:17]=2[CH2:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[S:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1Cc2sccc2CN1
Product: CC1Cc2sccc2CN1C(=O)c1cc2ncc(Br)cn2n1
Yield: 62 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH2:8][OH:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[CH:11]=2)[CH:3]=1.N1C=CN=C1.[C:23]([Si:27](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[N:6]([CH2:7][CH2:8][O:9][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH3:17])[CH:11]=2)[CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CNc1cc(-c2cc(N)n(CCO)n2)ccn1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CNc1cc(-c2cc(N)n(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)ccn1
Reaction time: 8 h
Yield: 100 %

Procedure:
Starting material 2-(5-amino-3-(2-(methylamino)pyridin-4-yl)-1H-pyrazol-1-yl)ethanol 30.A was prepared analagously to example 23.1. To a flask with 30.A (306 mg, 1.3 mmol) was added DMAP (16 mg, 0.13 mmol), 1H-imidazole (268 mg, 3.9 mmol). Then DMF 1.5 mL was added, followed by tert-butylchlorodiphenylsilane (505 mg, 1.8 mmol). The reaction was stirred overnight. Standard aqueous workup and silica gel chromatography afforded 618 mg (100%) 30.B.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23]I)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:25])[CH:16]([CH2:21][CH2:22][CH2:23][S:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCI)C(=O)OC)cc1
Reactant: Sc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCSc2ccc(Cl)cc2)C(=O)OC)cc1
Yield: 80.6 %

Procedure:
A solution of 0.958 g (2.0 mmol) of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-5-iodopentanoate, 0.35 g (2.4 mmol) of 4-chlorobenzenethiol, and 0.323 g of diisopropylethylamine in 50 ml of isopropyl alcohol was stirred at room temperature for 18 hours. Evaporation of solvent gave 0.8 g of methyl 2-[{[4-(2-butynyloxy)-phenyl]sulfonyl}-(methyl)amino]-5-[(4-chlorophenyl)sulfanyl]-pentanoate as colorless crystals, mp 88-89° C., Electrospray Mass Spec 496.1 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:13].[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:15][CH:16]=1
Reactant: O=C(CCCCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 5-chloro-1-(4-fluorophenyl)-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 425.2 (M+H)+.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12]CCCCCCO>C1(C)C=CC=CC=1>[C:1]1(=[O:6])[NH:12][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCCO
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21

Procedure:
A solution of phthalic anhydride (32.0 g, 0.21 mol) and 6-aminohexanol (25.0 g, 0.21 mol) in 180 mL dry toluene was heated to reflux for 3 hrs. When the intermediate phthalimide was formed, PBr3 (18.2 mL, 0.58 mol in 20 mL toluene) was added dropwise and the reaction was stirred at 100° C. for 1.5 hrs. The reaction mixture was filtered thru a microfiber filter and the filtrate was concentrated in vacuo to give the crude product which then crystallized from toluene to give 6-phthalimido-1-bromohexane. (86% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].N1C=CN=C1.Cl[Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([O:11][CH3:12])[C:5]=1[O:13][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(Br)cc(OC)c1O
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1cc(Br)cc(OC)c1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
After dissolving 3 g of 2-allyl-4-bromo-6-methoxyphenol in 10 ml of DMF, 1.3 g of imidazole and 2 g of chlorotriisopropylsilane were added and the mixture was stirred at 50° C. for 4 hours. Next, 1N hydrochloric acid was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give (2-allyl-4-bromo-6-methoxyphenoxy)triisopropylsilane.
Reaction SMILES: N=C=N.[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[CH:18]\[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)/[C:15]([OH:17])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].C1C=CC2N(O)N=NC=2C=1.[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1[NH2:39]>CN(C=O)C>[CH3:4][S:5]([C:8]1[CH:9]=[CH:10][C:11](/[C:14](=[CH:18]\[C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)/[C:15]([NH:39][C:35]2[S:34][CH:38]=[CH:37][N:36]=2)=[O:17])=[CH:12][CH:13]=1)(=[O:6])=[O:7]
Reactant: Nc1nccs1
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)O)cc1
Agent: N=C=N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(=C\c2ccsc2)C(=O)Nc2nccs2)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A suspension of PS-carbodiimide (688 mg, loading 1.34 μmol mg−1, 922 μmol), (E)-2-(4-methanesulfonylphenyl)-3-thiophen-3-ylacrylic acid (Preparation 1, 139 mg, 450 μmol), and HOBt (84 mg, 622 μmol) in anhydrous DMF was stirred for 15 min at 20° C. Thiazol-2-ylamine (32 mg, 320 μmol) was added, then the mixture was stirred for 40 h at 20° C., before being filtered through Celite. The filter cake was washed with DMF (10 mL), EtOAc (20 mL), and CH2Cl2 (20 mL). The solutions were combined, the solvents removed under reduced pressure, and the residue dissolved in EtOAc (50 mL). The EtOAc solution was washed with saturated aqueous Na2CO3 (3×20 mL), H2O (20 mL), and brine (20 mL), before being dried (Na2SO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 3:1 to 1:3) gave the title compound: RTA=3.43 min; m/z (ES+)=391.0 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:11])[CH:4]=[N:3][CH:2]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:4]=[N:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc2cncnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccc2cncnc12)c1ccccc1
Yield: 25.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, quinazolin-8-ylamine (Intermediate 480) (60 mg, 0.41 mmol), benzene sulfonyl chloride (94 mg, 0.53 mmol), DMAP (cat.) and pyridine (1 ml) at 150° C. for 2.5 h, gave title compound (30 mg, 54%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].C[O:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.Cl>C1COCC1>[CH2:20]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:13](=[O:12])[CH2:6][C:7](=[N:9][OH:10])[CH3:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)=NO
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CC(=O)[C@@H]1CCCN1Cc1ccccc1)=NO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 12.5 ml BuLi (1.6 M in hexane) was added a solution of 0.73 g acetone oxime in 8 ml THF at 0° C. After 30 minutes a solution of 1.0 g (S)-1-Benzyl-pyrrolidine-2-carboxylic acid methyl ester in 5 ml THF was added dropwise over a period of 20 minutes at this temperature. The resulting suspension was stirred for another 3 h at 0° C. before being cannulated into 21 ml 3 M HCl. The phases were separated; the aqueous phase was brought to pH8 using solid NaHCO3 and extracted with dichloromethane (3×) to give the crude product. Yield: 1.3 g mixture of E/Z isomers.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][N:10]2[CH3:16])=[CH2:5])C.O>C1COCC1.Cl>[F:15][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:16])=[C:6]([C:4](=[O:3])[CH3:5])[CH:14]=1
Reactant: C=C(OCC)c1cc(F)cc2c1cnn2C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cc(F)cc2c1cnn2C
Yield: 55.6 %

Procedure:
A solution of 4-(1-ethoxyvinyl)-6-fluoro-1-methyl-1H-indazole (1.24 g, 5.62 mmol) in THF (10 mL) and aqueous HCl (2.0 N, 10 mL) was stirred at RT for 2 h then poured into water (200 mL) and extracted with EtOAc (2×50 mL). The combined extracts were washed with an aqueous NH4OH (30 mL) and brine (50 mL), dried (MgSO4), filtered, and evaporated in vacuo to afford 1-(6-fluoro-1-methyl-1H-indazol-4-yl)ethanone as a white solid (600 mg, 55%). MS (ESI): m/z=193.2 [M+1]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1>[Si:1]([O:18][CH2:19][CH2:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][O:23]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: CC(C)(C)[Si](OCCCC=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OCCCC1NCCO1)(c1ccccc1)c1ccccc1
Reaction time: 1.5 h

Procedure:
A mixture of the 4-(tert-butyldiphenylsilyloxy)butanal (235 mg, 0.72 mmol) in benzene (3 ml) was added dropwise to a solution of hydroxy ethylamine (44 μL, 0.72 mmol) in benzene (3 mL). Powdered molecular sieves (4 Å, 600 mg) were added and the mixture was stirred for 1.5 h, before being filtered through a 20 μm Millipore syringe filter and concentrated. This gave 12 which was used directly and immediately in the synthesis of 13 (infra): 1H NMR(C6D6); δ1.18 (s, 9H), 1.65-1.82 (m, 2H), 2.62 (m, 2H), 3.33 (dd, 3H, J=6.1, 7.5 Hz), 3.69 (t, 3H, J=6.1 Hz), 4.26 (t, 1H), 7.23 (dd, 6H, J=1.9, 3.1 Hz), 7.79 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[I:22]I>C1COCC1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([I:22])=[C:10]([F:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(F)cc(-c2cccc(Cl)c2)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2cccc(Cl)c2)cc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
A RBF was charged with 3′-chloro-3-fluoro-5-methoxy-1,1′-biphenyl (577.6 mg, 2.441 mmol) and THF (8135 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 10 min, then n-butyllithium (1.8M in hexanes) (1627 μl, 2.93 mmol) was added dropwise. After 30 min, a solution of iodine (929 mg, 3.66 mmol) in THF (3 mL) was added dropwise. TLC after 5 min showed conversion to a slightly lower spot. The mixture was diluted with saturated aq. sodium thiosulfate solution and warmed to room temperature. The mixture was diluted with water and extracted with EtOAc (2×), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (25-g Ultra SNAP column, 0-5% EtOAc/Heptane) to give 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (687 mg, 1.895 mmol, 78% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) □=7.87 (td, J=1.0, 1.8 Hz, 1 H), 7.74 (td, J=1.8, 7.0 Hz, 1 H), 7.55-7.43 (m, 2 H), 7.25 (dd, J=1.8, 9.1 Hz, 1 H), 7.14-7.07 (m, 1 H), 3.97 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18](OCC)=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25].Cl.[NH2:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([NH:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:19])[C:8](=[O:17])[C:9]32[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:4][C:3]=1[O:24][CH3:25]
Reactant: CCOC(=O)C1=C(O)c2cc(OC)c(Br)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C1(CCOCC1)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C2O
Temperature: 95 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A mixture of ethyl 7-bromo-4-hydroxy-6-methoxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (0.28 g, 0.68 mmol) and tert-butyl 2-aminoacetate hydrochloride (0.17 g, 1.0 mmol) in 5 mL dioxane was treated with DIPEA (0.26 g, 2.0 mmol). The mixture was warmed to 95° C. and stirred for 3 hours, M+1=496/498. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc/hexane to give 0.28 g of the title compound as a white yellow solid. MS m/e=496/498 (M+H)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[O:5]=[C:6]([CH3:19])[CH2:7][C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9].N1CCCCC1.Cl>O>[C:6]([C:7](=[CH:1][CH2:2][CH3:3])[C:8]([O:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[O:9])(=[O:5])[CH3:19]
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Reactant: CCC=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)C(=CCC)C(C)=O
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a magnetically stirred, 1000 mL, round bottom flask were added 200 mL of propionaldehyde and 587 mL 2-(methacryloyloxy)ethyl 3-oxobutanoate. The reaction mixture was cooled to 0° C., in an ice bath, and then 3 to 5 mL of piperidine was added dropwise over one minute. The mixture was stirred at 0° C., for 2 hours, and then allowed to warm to room temperature over the course of 2-2.5 hours. To the reaction mixture was slowly added 30 mL of 3N HCl, over about one minute, to neutralize the piperdine. The mixture was poured into a separatory funnel, and then 150 mL of deionized water was added. The mixture was shaken, and then the aqueous layer was separated and disposed of. The reaction mixture was washed three more times with 150 mL of deionized water, each time, and then dried over MgSO4. The reaction mixture was filtered, and then stabilized with 10 mass ppm of 4-hydroxy-TEMPO. The dried reaction mixture was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-ethoxy-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M37) (203 mg, 0.38 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (148 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CSc1ccc(Br)cn1
Temperature: 10 °C
Yield: 104 %

Procedure:
A mixture of 2,5-dibromopyridine (7) (1100 g, 4.64 mol), tetrabutylammonium bromide (55 g, 0.037 equivalent) and a 15% aqueous sodium thiomethoxide solution (2387 g, 1.1 equivalent) was heated at 85 to 90° C. for 3.5 hours. After the reaction mixture was cooled to 10° C., the resulting solid was filtered off. The organic layer was washed with cold water (1 L) and concentrated to obtain the crude product (8) (985 g, yield 104%). The crude product (8) (908 g) was purified by recrystallization using 2-propanol (2.1 L) and water (4.2 L) to obtain a compound (8) as crystals (831 g, yield 91.5%).