Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:14]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:20][N:19]1[C:15]([C:14]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:16][N:17]=[CH:18]1
Reactant: COC(=O)c1cc2ccccc2cc1-c1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cncc1-c1cc2ccccc2cc1C(=O)O
Reaction time: 20 h
Yield: 74.3 %

Procedure:
A solution of methyl-3-(1-methyl-imidazol-5-yl)-2-naphthoate (Preparation 14) (8.5 g, 32 mmol) in THF/MeOH (3/2, 120 mL) was treated with aqueous NaOH (1.0 N, 48 mL). After 20 hours at RT, it was neutralized with aqueous HCl (1.0 N, 20 mL). The solvent was evaporated in vacuo. The solid residue was treated with MeOH (5 mL), then evaporated again. The resulting crude material was purified by flash chromatography (5% MeOH/EtOAc) affording the title compound as a pale-yellow solid (6.0 g, 74%). 1H NMR(CDCl3): 8.34 (s, 1H), 7.95 (d, J=8.1, 1H), 7.90 (d, J=8.1, 1H), 7.72 (s, 1H), 7.53 (s, 1H), 7.52 (m, 1H), 7.50 (m, 1H), 6.83 (s, 1H), 3.16 (s, 3H). (ESI) m/z (M+H)+=253.10.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=[C:35]([N:37](C)[CH3:38])C=CC=1B(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:37]([CH3:38])[CH3:35])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CN(C)c1ccc(B(O)O)c(Cl)c1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(N(C)C)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 2-chloro-4-dimethylaminophenylboronic acid and making non-critical variations provided the title compound as a pale yellow amorphous solid. IR (diffuse reflectance) 2969, 2932, 1607, 1567, 1550, 1486, 1443, 1391, 1353, 1225, 1207, 1177, 1043, 961, 740 cm−1; OAMS ESI+ 437.2; MS (EI) m/z 436 (M+); HRMS (FAB) calcd for C25H29CLN4O+H1 437.2108, found 437.2089. [α]25D=−7 (c 0.70, methylene chloride); Anal. Calcd for C25H29ClN4O: C, 68.72; H, 6.69; N, 12.82. Found: C, 68.48; H, 6.84; N, 12.66.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][C:15](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[OH:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][NH:50][CH2:49][CH:46]1[CH2:47][O:48][C:43]2[CH:42]=[CH:41][C:40]([OH:39])=[CH:51][C:44]=2[O:45]1
Reactant: COc1ccc2[nH]cc(CCCC(=O)O)c2c1
Reactant: NCC1COc2ccc(O)cc2O1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]cc(CCCCNCC3COc4ccc(O)cc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
5-Methoxyindole-3-butyric acid (1.5 g, 6.4 mmole), 1-hydroxybenzotriazole hydrate (1.0 g, 7.7 mmole) and 1,3-diisopropylcarbodiimide (2.4 ml, 15.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using first ethyl acetate and then 5% methanol in ethyl acetate as eluants. Evaporation of product-containing fractions gave 1.6 g (63%) of the desired product, (7-hydroxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-methoxy-1H-indol-3-yl)-butanamide, as an oily solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1([NH2:30])[CH2:29][O:28][CH2:27]1>>[CH3:25][C:26]1([NH:30][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:29][O:28][CH2:27]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2(C)COC2)n(C)n1
Yield: 95 %

Procedure:
As described for example 3, 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol), was converted, using 3-methyl-3-oxetanamine instead of 4-aminotetrahydropyran, to the title compound (98 mg, 95%) which was obtained as a white solid. MS: m/e=401.3 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.CN([CH:41]=[O:42])C.O=P(Cl)(Cl)Cl.[OH-].[K+].O>ClCCCl.CN(C=O)C>[CH:10]1[C:11]2[N:12]([C:14]3[N:15]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][C:29]([CH:41]=[O:42])=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:17]=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: c1cc(-n2c3ccccc3c3ccccc32)nc(-n2c3ccccc3c3ccccc32)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)c1ccccc1n2-c1cccc(-n2c3ccccc3c3ccccc32)n1
Temperature: 110 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a solution of 2,6-di(carbazol-9-yl)pyridine, prepared above in step 1, (10.0 g, 24.4 mmol) in 1,2-dichloroethane (80.0 ml) was slowly added POCl3/DMF (32.0 g/16.0 g). POCl3/DMF was made by the addition of POCl3 into DMF at 0° C. at room temperature under nitrogen atmosphere and stirring. After the addition of POCl3/DMF, the reaction mixture was heated to 110° C. and kept at this temperature for 72 hours. After cooling, the reaction mixture was slowly added into an ice-bath cooled KOH water solution (500.0 ml of water with 100 g of KOH). After addition, the reaction mixture was stirred for 60 minutes. The water solution was extracted with ethyl acetate (3×100 ml). The organic extracted solution was washed with water until a pH=7 was obtained. The removal of solvent, crude product was purified by silica gel column with dichloromethane:hexanes:ethyl acetate (5:4.5:0.5) as the solvent mixture. After removal of the solvent mixture, the product was recrystallized from THF/water to give 4.3 g (40.3%) of pure product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[S-:16][C:17]#[N:18].[NH4+].ClCl>CO>[CH3:12][C:11]([C:7]1[CH:8]=[C:9]([S:16][C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])[CH3:13]
Reactant: N#C[S-]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: ClCl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Temperature: 0 °C

Procedure:
To a three-necked, round bottom 5 L flask, equipped with a mechanical stirrer, gas inlet, thermometer and gas inlet, thermometer and gas outlet, was added 2,6di-tert-butylphenol (474 g, 2.30 mole), ammonium thiocyanate (76.12 g, 4.83 mole) and methanol (1200 ml). The reaction mixture was stirred and cooled to 0° C. in an ice/salt bath. Maintaining the temperature at 0° to 10° .C, chlorine gas was slowly bubbled through the mixture for about 1 hour whereupon the reaction mixture was a heterogeneous yellow color. Ammonia was then bubbled h the reaction for about 11/2 hours, maintaining the reaction mixture at a temperature of between 0° to 10° C. The reaction was stirred for an additional hour at 0° C., poured into 2 L of cold distilled water and refrigerated overnight. The aqueous phase was decanted and the solid taken up in methanol, precipitated from water, filtered and dried for 2 days over phosphorous pentoxide. The resulting gummy yellow solid was recrystallized from pentane and dried in vacuo to yield the product as a white powder, m.p. 61.5°-63° C. Analysis calc. for C15H21NSO: Theory: C, 68.40; H, 8.03; N, 5.32; S, 12.17. Found: C, 68.85; H, 8.05; N, 5.29; S, 12.12.
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[C:41]1([N:47]=[C:48]=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[C:50]([O:54][CH2:55][CH2:56][OH:57])(=[O:53])[CH:51]=[CH2:52].[N-]=C=O>>[C:50]([O:54][CH2:55][CH2:56][O:57][C:48](=[O:49])[NH:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=[O:53])[CH:51]=[CH2:52]
Reactant: O=C=Nc1ccccc1
Reactant: C=CC(=O)OCCO
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Product: C=CC(=O)OCCOC(=O)Nc1ccccc1
Temperature: 60 °C

Procedure:
A 500 ml round-bottom flask was initially charged with 0.25 g of 2,6-di-tert-butyl-4-methylphenol, 0.12 g of Desmorapid Z, 126.4 g of phenyl isocyanate, and the mixture was heated to 60° C. Subsequently, 123.3 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept at 60° C. until the isocyanate content had fallen below 0.1%. This was followed by cooling. The product was obtained as a crystalline solid (preparation described in DE 2329142).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH2:8][CH2:9]2)C.[Na]>CO.O>[CH3:1][O:3][C:4](=[O:34])[CH2:5][C:6]1([OH:33])[CH2:11][CH:10]2[C:12]([CH3:14])([CH3:13])[C:7]1([CH2:15][S:16]([N:19]1[CH2:24][CH2:23][C:22]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25]3)[CH2:21][CH2:20]1)(=[O:17])=[O:18])[CH2:8][CH2:9]2
Reactant: CCOC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)CC1(O)CC2CCC1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1S(1.Alpha.,2α,4α))-2-hydroxy-7,7-dimethyl-1-((spiro(1H-indene-1,4'-piperidin)-1'-yl sulfonyl)methyl)bicyclo(2.2.1)heptane-2-acetic acid ethyl ester (45 mg, 0.092 mmol) was stirred in a mixture of methanol (1 ml) and water (1 ml) and treated with sodium hxdroxide (0.1 ml of a 5N solution in water; 0.5 mmol). The mixture was stirred for 1 hr at ambient temperature, then evaporated to dryness in vacuo. The residue was treated with saturated sodium bicarbonate solution and extracted with ether. The ether layer was evaporated to dryness in vacuo and the residue was chromatographed on a silica gel column eluted with 15% EtOAc in hexane. The product fractions were evaporated to dryness in vacuo, and the residue was triturated with CH2Cl2 and again evaporated to dryness. The residue was dried in vacuo at ambient temperature overnight to give the title compound: (mp 81°-83°).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:19]([C:23]1[CH:29]=[CH:28][C:26](N)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].[K+].[Br-].[CH2:32](Cl)Cl.CCOC(C)=O>>[C:19]([C:23]1[CH:29]=[CH:28][C:26]([CH2:32][NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: ClCCl
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CNc2ncnc3ccc4nc(C#N)sc4c23)cc1
Yield: 99 %

Procedure:
Prepared from VII and 4-tert-butylaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 99%; yellow solid; mp 154° C.; IR (KBr) νmax/cm−1 2958, 2235, 1693, 1649, 1582, 1505, 1466, 1408, 1349, 1288, 1219, 1155, 1125, 989, 968, 894, 831; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=9.0 Hz), 8.07 (s, 1H), 7.76 (d, 1H, J=9.0 Hz), 7.40 (d, 2H, J=7.8 Hz), 7.12 (m, 2H), 1.31 (s, 9H); HRMS calcd for C20H18N5S (M+H+): 360.1283, found 360.1273.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1.[CH2:30]([C:32]([CH2:39][CH3:40])([CH2:36][CH:37]=[CH2:38])[C:33](Cl)=[O:34])[CH3:31]>>[CH2:30]([C:32]([CH2:39][CH3:40])([CH2:36][CH:37]=[CH2:38])[C:33]([O:1][C@@H:2]1[C@H:11]2[C:6]([CH:7]=[CH:8][C@H:9]([CH3:29])[C@@H:10]2[CH2:12][CH2:13][C@H:14]2[O:19][C:18](=[O:20])[CH2:17][C@H:16]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[CH2:15]2)=[CH:5][CH2:4][CH2:3]1)=[O:34])[CH3:31]
Reactant: C=CCC(CC)(CC)C(=O)Cl
Reactant: C[C@H]1C=CC2=CCC[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C=CCC(CC)(CC)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 77.5 %

Procedure:
A procedure similar to that described in Example 6, above, was followed, but using 1.26 g (3.0 mmol) of (4R,6R)-6-{2-[(1S,2S,8S,8aR)-1,2,6,7,8,8a-hexahydro-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Japanese Patent Kokai Application No. Sho 59-175450] and 2.09 g (12.2 mmol) of 2,2-diethyl-4-pentenoyl chloride, to provide 1.30 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=1.[C:19]([CH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)([CH3:22])([CH3:21])[CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[C:19]([C@@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([NH2:18])=[O:17])[CH:11]=3)=[C:2]([F:1])[CH:7]=2)[CH2:27][CH2:28]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: NC(=O)c1cccc(-c2ccc(C=O)cc2F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[C@H]1CC[C@@H](NCc2ccc(-c3cccc(C(N)=O)c3)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 2′-fluoro-4′-formylbiphenyl-3-carboxylic acid amide (Preparation 9, 252 mg, 1.0 mmol) in DCM (100 mL) was added 4-tert-butylcyclohexylamine (500 μL, 3.2 mmol), acetic acid (200 μL, 3.5 mmol) and sodium triacetoxyborohydride (648 mg, 3.1 mmol). The mixture was stirred at rt for 16 h. EtOAc (100 mL) was added and the organics washed with aqueous NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (17% EtOH: Toluene) to give cis-4′-[(4-tert-butylcyclohexylamino)methyl]-2′-fluorobiphenyl-3-carboxylic acid amide: RT=2.84 min; m/z (ES+)=383.0 [M+H]+, and trans-4′-[(4-tert-butylcyclohexylamino)methyl]-2′-fluorobiphenyl-3-carboxylic acid amide: RT=2.87 min; m/z (ES+)=383.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I[CH3:18]>O1CCCC1.O>[CH3:18][O:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (1.19 g, 60% in mineral oil, 29.7 mmol) was added portionwise to a cooled (10° C.) solution of tert-butyl 4-hydroxy-1-piperidinecarboxylate (Bioorg. Med. Chem. Lett. 10; 24; 2000; 2815) in tetrahydrofuran (80 mL), and the suspension stirred at room temperature for 1 hour. Iodomethane (1.85 mL, 29.7 mmol) was added, and the reaction stirred at 50° C. for 20 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (2×150 mL) and the combined organic extracts washed with saturated sodium bicarbonate solution (50 mL), dried (MgSO4) and evaporated under reduced pressure, to afford the title compound as a golden oil, 5.24 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.S(=O)(=O)(O)O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Br)cc1I

Procedure:
4-Bromophenol (51.9 g, 0.30 mol) and N-iodosuccinimide (67.5 g, 0.30 mol) were combined in acetic acid (360 mL). The mixture was stirred briefly, treated with concentrated sulfuric acid (5 mL, 0.09 mol) and stirred at about 22° C. overnight. The mixture was poured into water (about 800 mL) with stirring to precipitate the product. The suspension was stirred for about 1 hour and filtered. The wet cake was washed with water (50 mL, 2×) and dried under reduced pressure at about 50° C. (80.9 g, 90%). MS-DEI (M+H)+ m/z at 298; 1H NMR (CDCl3 at 400 MHz) δ 5.28 (s,1H), 6.86 (d, 1H), 7.33 (dd, 1H), 7.75 (d, 1H); 13C NMR (CDCl3 at 100 MHz) δ 86.0, 112.8, 116.0, 132.7, 139.4, 153.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:51][CH:52]([NH:61][C:62]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[O:63])[CH2:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=O)=O)=CC=1>>[CH2:65]([O:64][C:62]([NH:61][CH:52]([CH2:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[CH2:51][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:10][CH:9]2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]3[O:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][CH2:37][O:38][CH3:39])[C:30]=3[CH:40]=2)=[CH:4][CH:3]=1)=[O:63])[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(CCc2ccccc2)NC(=O)OCc2ccccc2)cc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCC(CCc4ccccc4)NC(=O)OCc4ccccc4)cc3)cc21

Procedure:
Analogously to Method I, 0.250 g of benzyl 4-(4-hydroxyphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 259b) and 0.281 g of 2-benzyloxycarbonylamino-4-phenylbutyl toluene-4-sulphonate are reacted. The title compound is obtained as a colourless oil. Rf=027 (2:1 EtOAc-heptane); Rt=6.01.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[C:15]1[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[NH2:25])C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:13])[C:15]3[C:16](=[CH:17][CH:18]=[C:19]([O:23][CH3:24])[C:20]=3[O:21][CH3:22])[NH:25][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(N)ccc(OC)c1OC
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=O)n(-c3ccc(Cl)cc3)c(=O)c2c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To p-chlorophenyl isocyanate (2.7 ml, 3.22 g, 20.97 mM) in pyridine (4.7 ml) at 0° C. was added a cold solution of 2-amino-5,6-dimethoxybenzoic acid ethyl ester (3.0 g, 13.32 mM) in pyridine (7.1 ml). The reaction mixture solidified shortly after the addition of the ester. The reaction mixture was allowed to go to room temperature but remained a solid. More pyridine (15 ml) was added and the pink slurry stirred at room temperature for three hours. The solvent was removed in vacuo to give a pink solid. The solid was triturated with 300 ml of 1N NaOH (4:1, MeOH:H2O) was added and the solution was heated at reflux for 2 hours. The solvent was removed in vacuo and the reddish solid partially dissolved in H2O (25 ml). The pH was adjusted to 5 with acetic acid and the resulting solid filtered, washed with H2O (~75 ml) and dried to give crude product as a pink solid. The crude product was triturated with MeOH. The insoluble solid was filtered to afford the title compound as a white solid; 2.66 g; mp 269°-273° C., CF3COOH(TMS), 7.10-7.77 (m, 6H, 7-H, 8-H, 9-H, 10-H, 12-H 13-H), 4.12 (s, 3H, 5 or 6-OCH3), 4.07 (s, 3H, 5 or 6-OCH3); M+ 332.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([NH2:26])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:26][C:15]2[CH:16]=[CH:17][C:18]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[C:13]([F:12])[CH:14]=2)=[N:4][CH:3]=1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3ncc(Br)n4ccnc34)cc2F)CC1
Yield: 4.8 %

Procedure:
Following the general procedure for amine displacement using 5,8-dibromoimidazo[1,2-a]pyrazine (0.50 g, 1.81 mmol), 3-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamine (0.45 g, 2.17 mmol) and DIPEA (0.47 mL, 2.72 mmol) in iPrOH (5 mL). The crude material is purified by silica gel column chromatography eluting with 90:10 DCM:MeOH to give the title compound (35 mg, 5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=C[C:20]2[N:25]([OH:26])N=NC=2C=1.[CH3:27]CN(C(C)C)C(C)C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:25]([O:26][CH3:27])[CH3:20])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: On1nnc2ccccc21
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 24.95 g 3-(4-bromophenyl)propionic acid, 12.75 g N, O-dimethylhydroxylamine hydrochloride, 27.14 g EDC, and 17.66 g HOBt were added 300 mL DMF and 47.4 mL DIEA. The reaction mixture was stirred at room temperature for 17 hours and then poured into 700 mL ice water, extracted with 5×200 mL EtOAc. The combined EtOAc solution was washed with 200 mL 5% NaHCO3, 4×200 mL water, and 200 mL saturated brine, dried over Na2SO4, and concentrated under reduced pressure to give crude product as a yellow oil. It was purified on silica gel using 35˜55% EtOAc in hexanes to give the title compound as yellowish oil. 1H NMR (CDCl3, 500 MHz) δ 7.40˜7.43 (m, 2H), 7.11˜7.14 (m, 2H), 3.63 (s, 3H), 3.19 (s, 3H), 2.93 (t, J=7.8 Hz, 2H), 2.73 (t, J=7.7 Hz, 2H). LC-MS: 1.77 min. (M+H=272.1/274).
Reaction SMILES: [NH:1]=[N+:2]=[N-:3].[F:4][C:5]1[CH:6]=[C:7]([C:12](O)([CH3:14])[CH3:13])[CH:8]=[C:9]([F:11])[CH:10]=1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:12]([C:7]1[CH:8]=[C:9]([F:11])[CH:10]=[C:5]([F:4])[CH:6]=1)([CH3:14])[CH3:13])=[N+:2]=[N-:3]
Reactant: CC(C)(O)c1cc(F)cc(F)c1
Reactant: [N-]=[N+]=N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1cc(F)cc(F)c1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
Hydrogen azide (2M in toluene, 1.5 mol) was added to the solution of 2-(3,5-difluoro-phenyl)-propan-2-ol (Preparation 50, 145 g, 0.84 mol, 1 eq) in chloroform (1 L) and the content of the flask was cooled to −5° C. The mixture of TFA (2.5 mol, 2.98 eq) with chloroform (1:1) was added dropwise at such a rate to keep the internal temperature below −5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirring was continued for 20 h. The reaction was poured into 2M sodium hydroxide and layers were separated. The aqueous phase was extracted two times with chloroform and combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the title compound was used in the next step without further purification (171 g, 0.87 mol, 100%).