Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:20][CH:17]([CH3:19])[CH3:18])[N:3]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:5]=1
Reactant: CC(C)N
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Solvent: CC(C)=O
Product: CC(C)Nc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a stirred solution of 5.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile in 100 ml of acetone, 2.3 grams of isopropylamine was added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The acetone was removed under reduced pressure, and the reaction mixture was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The solution was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 2.7 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-isopropylamino-5-pyrimidinecarbonitrile; mp, 144°-147°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+]([O-])=O)[C:3]=1/[CH:12]=[CH:13]/[N:14](C)C.[OH-].[Na+]>C(O)(=O)C.O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:12]=[CH:13][NH:14]2
Reactant: CN(C)/C=C/c1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)c2cc[nH]c2c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 12.9 %

Procedure:
To a solution of crude[(E)-2-(2-bromo-4-fluoro-6-nitrophenyl)ethenyl]dimethylamine (D15) (6.07 g, 21.0 mmol) in acetic acid (200 mL) and water (50.0 mL) at 75° C. was added zinc powder (15.11 g, 231 mmol) portionwise over 1 hour. The mixture was heated to 85° C. and stirred for 4 hours. After cooling to room temperature, the reaction mixture was neutralised by the addition of 50% aqueous sodium hydroxide solution. The product was extracted into diethyl ether. After separation of the layers, the aqueous phase was re-extracted with diethyl ether. The combined organic layers were dried over magnesium sulphate, filtered and concentrated. The product was partially purified by silica gel chromatography eluting with 5-30% ethyl acetate in hexane. Purer fractions were combined to give the title compound (D16), (580 mg).
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[C:19]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[OH:1][C@@H:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2cccc3ccccc23)CC1

Procedure:
The reaction was performed in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (5.8 g) and 4-(naphthalen-1-yl)piperidine (5.0 g) in methanol (100 ml) and the obtained oil was treated with ethyl acetate/p-toluenesulfonic acid to give the title compound (7.8 g), melting point 119–121° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.S(Cl)([Cl:16])=O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ncc(C(=O)O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: Nc1ncc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
6-amino-5-nitro-nicotinic acid (2.50 g, 13.7 mmol) was mixed with 50 mL thionyl chloride and refluxed for 2 h. The mixture was concentrated and the residue reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][C:6]1[C:7]([Cl:19])=[N:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:10][C:11]=1Cl.[K+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([NH-:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.O>CS(C)=O>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:11]2[C:6]([O:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[O:2][CH3:1])=[C:7]([Cl:19])[N:8]=[C:9]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[N:10]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S([NH-])(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
2 g 5-(o-methoxyphenoxy)-4,6-dichloro-2-(4-pyridyl)-pyrimidine was dissolved in 30 ml dry DMSO. 2.40 g p-toluene-sulfonamide potassium salt was added and stirring continued for 20 h. The reaction mixture was poured onto 200 ml water and extracted twice with 200 ml diethylether. The combined organic layers were extracted twice with 50 ml water. The combined water layers were acidified by acetic acid to pH=4. The precipitated product was filtered off, washed with ether and dried under reduced pressure. 1.9 g p-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]benzene-sulfonamide was obtained as a slightly colored solid. Rf (EA/Hex=1/1)=0.15.
Reaction SMILES: [CH3:1]C1C(C)=NC(C)(C)CN=1.C=O.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14].CNC.[P:31]([O:38]CC)([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34]>>[C:23]([C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=1[OH:27])[CH2:1][P:31](=[O:38])([O:35][CH2:36][CH3:37])[O:32][CH2:33][CH3:34])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOP(OCC)OCC
Reactant: CC1=NCC(C)(C)N=C1C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: C=O
Agent: CNC
Product: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Temperature: 85 °C
Reaction time: 1 h

Procedure:
3.2 g of HTMP (hydroxymethylpiperidine), 52.3 g of paraformaldehyde and 206.3 g of 2,6-di-tert-butylphenol are rendered inert and are initially introduced at 60° C. under reduced pressure into a double-jacketed flask with an outlet at the bottom, a baffle, an impeller stirrer and a sublevel air lock for gas introduction. 52 g of dimethylamine gas are introduced at this temperature and the mixture is stirred at 85° C. for 1 hour. Addition of 332 g of triethyl phosphite is then carried out, after which the reaction mixture is kept at 115° C. for 4 hours. Working-up:distillation of triethyl phosphite and dimethylamine under reduced pressure and crystallization of the residue from ligroin yield 320 g of product (90%), melting point 114° C.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.S1[CH2:17][CH2:16][C:15](=[O:18])NC1=O.[OH-].C([N+:28](CCCC)(CCCC)CCCC)C1C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1>C(OCC)(=O)C>[CH:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH2:3][C@H:2]([NH:1][C:15]([CH2:16][CH2:17][NH2:28])=[O:18])[C:9]([OH:11])=[O:10]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Reactant: O=C1CCSC(=O)N1
Agent: O=S(=O)(O)c1ccccc1
Agent: [OH-]
Solvent: CCOC(C)=O
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O

Procedure:
Starting with 1.55 g. (10 mmol) of L-histidine, 2.62 g. (20 mmol) of tetrahydro-1,3-thiazin-2,4-dione, 40% methanolic benzyltri-n-butylammonium hydroxide solution to raise the pH benzenesulfonic acid to lower the pH and ethyl acetate as the crystallizing solvent, and following the procedure of Example 1, there is isolated L-carnosine in good yield.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2OS(C(F)(F)F)(=O)=O>C(Cl)(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 1-(3-Phenyl-allyl)-piperidin-4-ylamine (4) (1.01 g,4.65 mmol) and diisopropylethylamine (1.63 mL, 9.3 mmol) in 10 mL CHCl3 was added a solution of compound 3 (1.1 g, 5.6 mmol) in 10 mL CHCl3. The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water and brine and dried with MgSO4. The yellow residue was triturated with a small volume of dichloromethane and filtered. The final product was converted to the HCl salt by addition of 4.0N HCl in dioxane to a suspension of the compound in dichloromethane. The solvent was removed by evaporation and the residue triturated with methanol to give the title compound (780 mg, 39%). 1H NMR (300 MHz, MeOD-d4) δ 1.92-2.22 (2H, m), 2.35-2.45 (2H, bd, J=11.8 Hz), 3.15-3.35 (2H, m), 3.65-3.75 (2H, bd, j=12.3), 3.85-4.0 (1H, m), 3.90-4.00 (2H, d, J=6.9 Hz), 5.46 (1H, s), 6.32-6.43 (1H, p, J=7.7 Hz), 6.92-6.98 (1H, d, J=16.2 Hz), 7.31-7.41 (4H, m), 7.52-7.54 (2H, m), 7.58-7.62 (1H, dd, J=2.0, 8.8 Hz), 8.148 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([N:28]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:29](Cl)=[O:30])[CH3:27]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][C:29]([N:28]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26][CH3:27])=[O:30])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN(Cc1ccccc1)C(=O)Cl
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Product: CCN(Cc1ccccc1)C(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC

Procedure:
Prepared according to the procedure described in Example 131, Step 2, using the following starting materials: (2′-aminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, N-ethyl-N-benzylcarbamoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:7][CH3:8])=[N:4][S:5][N:6]=1.S(Cl)([Cl:12])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:7][CH2:8][Cl:12])=[N:4][S:5][N:6]=1
Reactant: COc1nsnc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCOc1nsnc1Cl
Yield: 79.3 %

Procedure:
A solution comprised of 5 g of 60 percent pure 4-chloro-3-methoxy-1,2,5-thiadiazole in 30 mL of carbon tetrachloride was irradiated over a period of 45 minutes at 80° C. with a sunlamp while adding a solution comprised of 5 g of sulfuryl chloride in 20 mL of carbon tetrachloride. The reaction mixture was then washed with 30 mL of asaturated aqueous sodium bicarbonate solution and concentrated under reduced pressure to yield 4.87 grams of 4-chloro-3-chloromethoxy-1,2,5-thiadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.Cl.[NH2:22][CH:23]1[CH2:30][CH:29]2[N:31]([CH3:32])[CH:25]([CH2:26][CH2:27][CH2:28]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:31]1[CH:25]2[CH2:26][CH2:27][CH2:28][CH:29]1[CH2:30][CH:23]([NH:22][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:19])[CH2:24]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cc(Cl)cc2oc(-c3ccccc3)nc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1C2CCCC1CC(NC(=O)c1cc(Cl)cc3oc(-c4ccccc4)nc13)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A 15-mL, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 6-chloro-2-phenyl-benzoxazole-4-carboxylic acid (0.075 g, 0.274 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (0.063 g, 0.411 mmol) 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (0.079 g, 0.411 mmol), 1-hydroxybenzotriazole (0.037 g, 0.274 mmol), diisopropylethylamine (0.141 g, 1.09 mmol), and DMF (1.0 mL). After stirring at ambient temperature for 18 h, the reaction was concentrated under reduced pressure and purified by preparative HPLC to afford 0.016 g (14% yield) of N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-phenylbenzoxazole-4-carboxamide as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 8.95 (br s, 1H), 8.23 (d, J=6.9 Hz, 2H), 8.20 (d, J=2.0 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.65-7.57 (m, 3H), 4.58 (q, J=7.1 Hz, 1H), 3.18 (br s, 2H), 2.58 (m, 5H), 2.25-2.02 (m, 3H), 1.55 (s, 3H), 1.23 (m, 3H); MS (APCI) m/z 409 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](COCC[Si](C)(C)C)[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.NCCN>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Oc3ccc(N)cc3F)ccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1
Temperature: 65 °C
Yield: 92.1 %

Procedure:
A mixture of 3-fluoro-4-(2-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (275 mg, 0.61 mmol), tetrabutylammonium fluoride (1 M in THF, 4 mL), and 1,2-diaminoethane (0.2 mL) in THF (4 mL) was heated at 65° C. for 24 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to afford the desired product (180 mg, 92%) as a yellow solid. LC/MS(ESI+) m/z 321 (M+H)+.
Reaction SMILES: C(OO)(C)(C)C.[OH-].[NH4+:8].[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:35])=[CH:17][C:18]([O:33][CH3:34])=[CH:19][C:20]=3[C:21]32[C:27]2=[N:28][CH2:29][CH2:30][CH2:31][N:26]2[C:25](=S)[NH:24]3)=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[CH:23]=[C:22]2[C:13]([O:14][C:15]3[C:16]([F:35])=[CH:17][C:18]([O:33][CH3:34])=[CH:19][C:20]=3[C:21]32[C:27]2=[N:28][CH2:29][CH2:30][CH2:31][N:26]2[C:25]([NH2:8])=[N:24]3)=[CH:12][CH:11]=1
Reactant: COc1cc(F)c2c(c1)C1(NC(=S)N3CCCN=C31)c1cc(Br)ccc1O2
Reactant: [NH4+]
Agent: CC(C)(C)OO
Agent: [OH-]
Solvent: CO
Product: COc1cc(F)c2c(c1)C1(N=C(N)N3CCCN=C31)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Tert-butyl hydroperoxide (70% in water) (1.945 mL, 20.08 mmol), ammonium hydroxide (13.03 mL, 335 mmol), and 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthene]-6(7H)-thione (300 mg, 0.669 mmol) were combined in MeOH (50 mL) and stirred at RT overnight. The solution was concentrated. The product was purified from the crude concentrate via silica gel column chromatography (RediSep 40 g column) using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford 7′-bromo-4′-fluoro-2′-methoxy-3,4-dihydro-2H-spiro[imidazo[1,5-a]pyrimidine-8,9′-xanthen]-6-amine (150 mg, 0.348 mmol). MS m/z=431.0 [M+H].
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19].CC1C=CN=C(N)C=1C>C(Cl)Cl>[CH3:21][S:18]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCO
Agent: Cc1ccnc(N)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 mg (1.08 mmol) of (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonanol was dissolved in dry DCM (10 ml) under argon atmosphere, followed by the addition of triethylamine (224 ul), MsCl (mesylchloride) (125 ul) and a catalytic amount of DMAP (dimethyl amino pyridine) at 0° C. After 15 minutes the cooling bath was removed and the reaction stirred at room temperature for 1.5 hours. TLC monitoring showed complete conversion in 100% DCM as mobile phase. Extraction with water and DCM afforded crude product that was obtained following evaporation of the solvent under reduced pressure. Column chromatography on silica (100% DCM) gave pure (R)-9-(6-tert-butyl-dimethyl-silanyloxy)-2,5,7,8-tetramethylchroman-2-yl)nonyl methanesulfonate in high yields (following high vacuum). (90%, 526 mg, 0.97 mmol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH2:9].C1(C)C=CC(S([N:26]=[N+:27]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C>>[CH3:1][O:2][C:3](=[O:16])[C:4](=[N+:26]=[N-:27])[C:5](=[O:15])[CH2:6][CH:7]([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH:8]=[CH2:9]
Reactant: C=CC(CC(=O)CC(=O)OC)O[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Product: C=CC(CC(=O)C(=[N+]=[N-])C(=O)OC)O[Si](C)(C)C
Yield: 83 %

Procedure:
In accordance with the process of Preparation 1, 3-oxo-5-trimethylsilyloxy-6-heptenoic acid methyl ester (360 mg; 1.47 mmol), p-toluenesulfonyl azide (290 mg; 1.47 mmol) and triethylamine (150 mg; 1.47 mmol) were used as starting materials to obtain 330 mg of 2-diazo-3-oxo-5-trimethylsilyloxy-6-heptenoic acid methyl ester as a yellow oily product.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(COC)OC>[Br:14][C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)=[CH:22][CH:23]=3)[C:18]([CH3:30])([CH3:29])[C:17]=2[CH:16]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(I)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4ccccc4c3)cc21
Reaction time: 8 h
Yield: 65.9 %

Procedure:
In argon atmosphere, a mixture of 13.91 g (80.9 mmol) of 2-naphthaleneboronic acid, 30.0 g (80.9 mmol) of 2-bromo-7-iodo-9,9-dimethylfluorene, 4.67 g (4.0 mmol) of tetrakis(triphenylphosphine)palladium (0), 200 ml of toluene, 200 ml of dimethoxyethane, and 122.36 g of a 2 M sodium carbonate aqueous solution was refluxed under stirring for 8 h and left standing overnight. After adding water, the mixture was stirred at room temperature for one hour. After filtration and extraction with toluene, the organic phase was washed with water and then with a saturated saline solution. After drying over sodium sulfate, the toluene was distilled off under reduced pressure. The residue was purified by silica gel chromatography to obtain 21.3 g (yield: 76.1%) of 2-bromo-9,9-dimethyl-7-(naphthalene-2-yl)-9H-fluorene.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][N:30]([C:40](=[O:42])[CH3:41])[CH2:29][CH2:28]4)[CH:26]=3)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Fluoro-6-[6-(1-piperidin-4-yl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-quinoline (Example 180, 50 mg, 0.117 mmol) and triethylamine (33 μL, 0.234 mmol) were dissolved in THF (1 mL). Acetyl chloride (9 mg, 0.117 mmol) was then added dropwise and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with a 4 g RediSep® silica gel column, DCM/(DCM/MeOH 9:1+NH3)=100:0→0:100) to afford the title compound as a foam (tR 3.50 min (conditions 3), MH+=470.2, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.51 (s, 1H); 8.34 (m, 1H); 8.09 (m, 2H); 8.04 (d, 1H); 7.76 (d, 1H); 7.60 (s, 1H); 7.53 (d, 1H); 7.47 (dd, 1H); 4.55 (s, 2H); 4.48 (m, 2H); 3.92 (m, 1H); 3.21 (m, 1H); 2.72 (m, 1H); 2.04 (m, 5H); 1.89 (m, 1H); 1.75 (m, 1H)).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].BrC1C=C(O)C=CC=1.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[C:28]2=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:38]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([OH:36])([C:3]3[C:2]([OH:11])=[CH:1][C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[CH:4]=3)[C:28]2=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCC2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 5,6,7,8-tetrahydro-2-naphthol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one was obtained (76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.52-7.49 (m, 1H), 7.32-7.28 (m, 10H), 7.09 (dd, J=5.6, 3.2 Hz, 2H), 6.95 (s, 1H), 6.75 (s, 1H), 6.51-6.48 (m, 2H), 4.31 (s, 1H), 2.70 (br s, 2H), 2.52 (br s, 2H), 1.72 (br s, 4H); MS (ES+) m/z 444.1 (M−17).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C@@H:14]2[CH2:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])=[CH:8][CH:7]=1.[Li+].[OH-].O.Cl>CO.C(OCC)(=O)C>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([S:24]([N:13]([CH2:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:11][CH:10]=2)[C@@H:14]2[CH2:20][C:19]([F:22])([F:21])[CH2:18][CH2:17][NH:16][C:15]2=[O:23])(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCc1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
3-(4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-phenyl)-propionic acid methyl ester (65 mg, 0.13 mmol) was dissolved in methanol (0.5 ml) and treated with 2 N LiOH in water (0.25 ml, 0.5 mmol) overnight at 40° C. The reaction mixture was distributed between 4 N HCl and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product (50 mg) was purified using column chromatography (dichloromethane/methanol 90:10) to yield 45 mg (71%);