Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:23]=[CH:22][C:16]4[N:17]=[C:18]([S:20][CH3:21])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][C:13]3[CH:23]=[CH:22][C:16]4[N:17]=[C:18]([S:20]([CH3:21])=[O:32])[S:19][C:15]=4[CH:14]=3)=[CH:10][N:11]=2)[N:8]=1
Reactant: COc1ccc2ncc(Cc3ccc4nc(SC)sc4c3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncc(Cc3ccc4nc(S(C)=O)sc4c3)n2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylthio)benzo[d]thiazole (500 mg, 1.46 mmol) in DCM (30 mL) was added m-CPBA (314 mg, 1.82 mmol) at 0° C. The reaction mixture was stirred for 2 h at 0° C., then aq Na2SO3 (15 mL) was added and the mixture was stirred for 0.5 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 50:1 to 20:1 DCM/MeOH to afford 6-((6-methoxyimidazo[1,2-b]pyridazin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole as a yellow solid (500 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 7.99-7.93 (m, 2H), 7.76 (d, J=9.6 Hz, 1H), 7.53 (dd, J=1.5, 8.4 Hz, 1H), 7.46 (s, 1H), 6.65 (d, J=9.3 Hz, 1H), 4.42 (s, 2H), 3.94 (s, 3H), 3.06 (s, 3H). LCMS (ESI) m/z 359 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[Na+].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][CH2:18][C:17](=O)[C:16]=2[CH:23]=1>O.C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[O:21][CH2:20][CH2:19][CH2:18][C:17](=[N:2][OH:3])[C:16]=2[CH:23]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCCO2
Reaction time: 24 h

Procedure:
6.95 g of hydroxylamine hydrochloride dissolved in 15 ml of water and 5.3 g of sodium carbonate are added to a solution of 19.2 g of 7-methoxy-3,4-dihydro-1-benzoxepin-5-one in 45 ml of ethanol. The mixture is left at room temperature for 24 hours with stirring. 100 ml of water are then added and the alcohol is evaporated. The aqueous solution is make alkaline by the addition of soda and unreacted benzoxepin is extracted with ether. The aqueous phase is neutralised and the desired oxime is extracted with ether. After drying of the organic solution and evaporation of the solvent under reduced pressure, a white solid is obtained which, when recrystallised from cyclohexane yields 17 g of the desired pure product which has a melting point of 103° to 104° C.
Reaction SMILES: [Br:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][CH2:7][CH:8]([OH:34])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.I[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([O:34][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)=[CH:35][CH:36]=1
Reactant: OC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1
Reactant: CCCCCI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCCOC(COc1ccc(Br)cc1)COc1ccc(C(CCCc2ccccc2)OC2CCCCO2)cc1

Procedure:
A mixture of the product (0.57 g) of Step 3, 0.3 mL of 1-iodopentane and 80 mg of Nail in 20 ml of 1:1 THF/DMF was refluxed for 4 hrs. The mixture was then quenched with 5 mL of MeOH, 20 mL of Sat. NH4Cl, and extracted with 50 mL of Et2O. The extract was dried over NaSO4 and concentrated. The residue was purified by flash chromatography eluted with EtOAc and hexanes (7:1) to give 0.6 g of the title compound.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:43])[C:33]1[CH:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1cc(OC)cc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
250 mg (0.423 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dimethoxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 64 mg (1.69 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR31## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.23, DCI-MS: (M+H)+ -496.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[S:13][C:12]([C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C1COCCN1
Reactant: CSc1nccc(-c2ccc(C(=O)O)s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nccc(-c2ccc(C(=O)N3CCOCC3)s2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A mixture of 5-(2-(methylthio)pyrimidin-4-yl)thiophene-2-carboxylic acid (200 mg, 0.79 mmol), morpholine (69 mg, 0.79 mmol), EDCI (182 mg, 0.95 mmol), HOAt (21 mg, 0.16 mmol) and triethylamine (159 mg, 1.58 mmol) in dichloromethane (20 mL) was stirred at rt for 24 h. Water (50 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with ethyl acetate/hexane (1:1) to give the intermediate (5-(2-(methylthio)pyrimidin-4-yl)thiophen-2-yl)(morpholino)methanone as a white solid (200 mg, 78%). MS (M+H)+ 322.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:12]3([CH3:39])[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:40]>>[NH2:40][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:27][C@H:26]([CH2:15][O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@H:28]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@:12]3([CH3:39])[O:13][CH3:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Product: CO[C@]1(C)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(N)ncnc21

Procedure:
To the compound from Step A (735 mg, 1.16 mmol) was added methanolic ammonia (saturated at 0° C.) (20 mL). The mixture was heated in a stainless steel autoclave at 80° C. overnight, then cooled and the content evaporated in vacuo. The crude mixture was purified on silica gel using ethyl acetate/hexane as the eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (504 mg) as colorless foam.
Reaction SMILES: [CH3:1][O:2][C@H:3]([C@@H:6]([C@H:9]([C@H:12]([CH3:14])[OH:13])[O:10][CH3:11])[O:7][CH3:8])[CH:4]=[O:5].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C@@H:3]1[C@H:6]([O:7][CH3:8])[C@@H:9]([O:10][CH3:11])[C@H:12]([CH3:14])[O:13][C@H:4]1[O:5][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22]
Reactant: CO[C@H]([C@@H](OC)[C@H](C=O)OC)[C@H](C)O
Reactant: O=C1CCC(=O)N1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON2C(=O)CCC2=O)[C@@H]1OC
Reaction time: 4 h
Yield: 51.8 %

Procedure:
To a stirred solution of 2,3,4-tri-O-methyl-L-rhamnose (6.5 g, 31.5 mmol) and N-hydroxysuccinimide (5.4 g, 47 mmol) in benzene (50 mL) was added p-toluenesulfonic acid (50 mg, cat.). The solution was heated to reflux and water (H2O) was collected using a Dean-Stark trap. After 4 h, the solution was cooled and the supernatant toluene layer was separated from a small amount of insoluble gum. The organic layer was washed with a saturated solution of sodium bicarbonate (NaHCO3; 20 mL), then dried over MgSO4 and concentrated to a solid. Recrystallization from ether (Et2O)-hexanes gave the title compound (4.95 g, 52%) as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH3:12])[CH2:5][CH2:4]1.[O:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1>>[F:28][C:2]([F:1])([F:27])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:10](=[O:26])[N:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[CH2:16][N:15]([C:35]([CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[O:36])[CH2:14]2)[CH3:12])[CH2:5][CH2:4]1
Reactant: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCOCC1
Product: CN(C(=O)OC1CCC(C(F)(F)F)CC1)[C@@H]1CN(C(=O)C2CCOCC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(3,4-dichloro-phenyl)-1-(tetrahydro-pyran-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester was prepared from [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-trifluoromethyl-cyclohexyl ester instead of [(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydropyran-4-yl-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 551.4 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[NH:10][N:9]=1.[CH2:23](Br)[CH3:24]>>[CH2:23]([N:10]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9]1)[CH3:24]
Reactant: CCBr
Reactant: Fc1ccccc1-c1n[nH]c(-c2ccccc2C(F)(F)F)n1
Product: CCn1nc(-c2ccccc2F)nc1-c1ccccc1C(F)(F)F

Procedure:
starting from 3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole and ethyl bromide there is obtained a mixture of isomeric N-ethyltriazoles and therefrom there are obtained pure 1-ethyl-3-(o-fluorophenyl)-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 72°-74° C.; and pure 1-ethyl-5-(o-fluorophenyl)-3-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, 1H-NMR(CDCl3): 1.51 (t, CH3), 4.23 (q, CH2), 7.05-8.1 (8 aromatic H);
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(F)c(F)c1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 917 mg (2.13 mmol) dissolved in toluene (20 mL) were added 0.69 mL (6.39 mmol) of 1-chloroethyl chloroformate and 1.09 mL (6.39 mL) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (20 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 464 mg (64%) of the title compound as a light yellow oil. ES-MS m/e: 339.1 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15](B4OC(C)(C)C(C)(C)O4)=[CH:14][N:13]3[CH:27]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].I[C:35]1[N:36]=[CH:37][N:38]([C:40]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[C:53]1([C:40]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:38]2[CH:39]=[C:35]([C:15]3[CH:16]=[CH:17][C:12]4[N:13]([CH:27]=[C:10]([C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[O:9])[N:11]=4)[CH:14]=3)[N:36]=[CH:37]2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: CC1(C)OB(c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)OC1(C)C
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2n1
Yield: 42.2 %

Procedure:
540 mg of N-phenyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxamide (Intermediate 5), 13 mL of dioxane, 6.8 mL of 2M sodium carbonate solution, 843 mg of 4-iodo-1-triphenylmethylimidazole and 86 mg of tetrakis(triphenylphosphine)-palladium are placed in a microwave tube. The mixture is heated for 10 minutes in a microwave machine set at 120° C., and then cooled and concentrated under reduced pressure. The residue is taken up in 100 mL of dichloromethane. After washing with water, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a gradient of cyclohexane and ethyl acetate (from 100/0 to 60/40). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure. The solid is crystallized from acetonitrile. The crystals are washed with acetonitrile and then with ethyl ether and then dried under vacuum to give 342 mg of 6-(1-triphenylmethyl-1H-imidazol-4-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [H-].[Na+:2].NC1C=CC=CC=1.[CH3:10][C:11]1[CH2:15][C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]>O1CCCC1>[CH3:10][C:11]1[CH:15]([Na:2])[C:14]([CH3:16])=[C:13]([CH3:17])[C:12]=1[CH3:18]
Reactant: [Na+]
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [H-]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 40 °C
Reaction time: 4 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (2.50 g) and aniline (0.237 g) were added to the solution of tetramethylcyclopentadiene (5.01 g) dissolved in tetrahydrofuran (28 ml), and stirred at 40° C. for 4 hours. Thus, tetramethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [CH:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl(O)(=O)(=O)=O>[C].[Pd].C(O)(=O)C>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:11][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CCC(=O)c1ccc(C2CCCCC2)cc1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: O=C(O)CCCc1ccc(C2CCCCC2)cc1
Yield: 102.7 %

Procedure:
A solution of 3-(4-cyclohexylbenzoyl)propionic acid (10.7 g), acetic acid (100 ml) and perchloric acid (2.3 ml) was hydrogenated in the presence of 5% palladium carbon (50% wet, 3.0g) at room temperature under ordinary pressure. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. After water (100 ml) was added, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and dried (MgSO4), after which the solvent was evaporated off, to yield 4-(4-cyclohexylphenyl)butyric acid (10.4 g, 100%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:18])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([C:37](Cl)=[O:38])=[CH:32][CH:31]=[CH:30]3)[CH:21]=1.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:37]([C:33]2[C:34]3[C:29](=[CH:28][C:27]([O:26][C:22]4[CH:21]=[C:20]([Cl:19])[N:25]=[CH:24][N:23]=4)=[CH:36][CH:35]=3)[CH:30]=[CH:31][CH:32]=2)=[O:38])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc2cc(Oc3cc(Cl)ncn3)ccc12
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2.9 g (12 mMol) 5-tert-butyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine and 3.8 g (12 mMol) 6-(6-chloropyrimidin-4-yloxy)-naphthalene-1-carbonyl chloride (described under Step 19.3) are dissolved in 10 ml CH2Cl2 and cooled to 0° C. 0.99 ml (12 mMol) Pyridine are added dropwise and after complete addition the reaction is allowed to warm to rt. It is stirred for 2 h at ambient temperature. The reaction is worked up by addition of 150 ml CH2Cl2 and aq. extraction with sat. Na2CO3 solution. The organic layer is subsequently washed with brine and dried. After removal of the solvents the remaining crude product is purified by flash chromatography (SiO2; hexanes/EtOAc, gradient 3:1 to 2:1) to give the title compound as a yellow solid: m.p.: 163-164° C.
Reaction SMILES: [CH3:1][C@@H:2]([OH:15])[C@H:3]([NH2:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.[NH:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:18]([C:21](O)=[O:22])[CH2:19][OH:20].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]1O.C1CCC(NC2CCCCC2)CC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[NH:17]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:18]([C:19]([NH:14][C@H:3]([C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[C@@H:2]([CH3:1])[OH:15])=[O:20])[CH2:21][OH:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: C[C@@H](O)[C@H](N)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Solvent: ClCCl
Product: C[C@@H](O)[C@H](NC(=O)[C@H](CO)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
47.0 g of H-Thr-OBzl. HCl in 300 ml of methylene chloride are added to a solution of 73.8 g of BOC-Ser-OH. Dicyclohexylammonium salt in 500 ml of methylene chloride and the mixture stirred for 10 minutes at room temperature and then cooled to -5°C. A solution of 40.1 g of dicyclohexylcarbodiimide in 90 ml of methylene chloride is added dropwise at this temperature. The mixture is stirred for 3 hours at -5°C and overnight at room temperature. After filtering off the dicyclohexylurea and dicyclohexylamine hydrochloride the solution is extracted by shaking three times with 0.1 N hydrochloric acid, twice with 20 % strength sodium chloride solution, once with 10 % strength sodium bicarbonate solution and twice with 20 % strength sodium chloride solution and is dried over sodium sulphate. The solution is concentrated to about 600 ml, cooled to 5°C and further dicyclohexylurea is filtered off. After evaporation to dryness, the residue is crystallised from ethyl acetate-hexane in order to purify it.
Reaction SMILES: C(OC([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=O)C.C[Mg+].[Br-]>C1COCC1.CCOCC>[OH:21][C:18]([C:6]1[C:7]([CH3:31])=[C:8]2[C:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)([CH3:19])[CH3:17]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 25 °C
Yield: 127.2 %

Procedure:
To a solution of compound 3A (124 mg, 0.30 mmol) in THF (5 mL) at 0° C. was slowly added a 3.0 M solution of MeMgBr in ether (0.40 mL, 1.20 mmol. The reaction was warmed to room temperature and then heated at 50° C. for 1 h. After cooling to room temperature, the reaction was quenched with EtOAc (20 mL) and saturated aqueous NH4Cl (20 mL) was added. The resulting two layers were separated and the organic layer washed with brine, dried over Na2SO4 and concentrated to an orange oil. This crude oil was purified by silica gel flash chromatography (eluted with 14-17% EtOAc/CH2Cl2) to give compound 145 as a yellow solid (76 mg, 64%). HPLC: 97% at 1.97 min (retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220 nm). MS (ES): m/z 399 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](Cl)([Cl:12])=[O:11]>>[Cl:12][C:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)=[O:11]
Reactant: O=C(Cl)Cl
Reactant: OCc1ccc(F)cc1
Product: O=C(Cl)OCc1ccc(F)cc1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 4-fluorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:12][C:4]1[NH:3][C:2]([CH3:1])=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc[nH]c1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(Br)[nH]c1C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (1.53 g) in tetrahydrofuran (20 mL) was added N-bromosuccinimide (1.78 g) at −78° C., and the mixture was stirred at the same temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at not more than 5° C. The residue washed with hexane to give the title compound as a colorless solid (yield 2.26 g, 97%).