Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([O:32]CCCC)=[O:31].C(=O)([O-])[O-].[K+].[K+]>>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:20])[C:8]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:29][C:30]([OH:32])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)n(C)c2c1
Reactant: CCCCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3OCC(=O)O)n(C)c2c1
Reaction time: 72 h
Yield: 90.6 %

Procedure:
A solution of intermediate 4 (4.00 g, 11.0 mmol), tent-butyl 2-bromoacetate (2.36 g, 12.1 mmol) and potassium carbonate (3.04 g, 22.0 mmol) was stirred at room temperature. After 72 h, the reaction mixture was concentrated under vacuum and the residue was partitioned between CH2Cl2 and water. The organic layer was dried and the residue was reconstituted in CH2Cl2 (20 mL) and TFA (20 mL) was added. After 2 h at room temperature, the reaction mixture was evaporated under vacuum to yield 4.2 g (90%) of {2-[3-cyclohexyl-6-(methoxycarbonyl)-1-methyl-1H-indol-2-yl]phenoxy}acetic acid 5: m/z=422 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:10]#[C:11][Si](C)(C)C)[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:11][NH:9][C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)C#Cc1nc(Br)c(Cl)nc1N
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc2[nH]ccc2nc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.2 %

Procedure:
To a stirred solution of 5-bromo-6-chloro-3-trimethylsilanylethynyl-pyrazin-2-ylamine (2.0 g, 6.58 mmol) in THF (28 mL) was added a 1 M solution of KOtBu in THF (7.24 mL, 7.24 mmol) slowly at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min and then warmed to room temperature. After 2 h, the mixture was concentrated in vacuo and the residue obtained was suspended in water (7.5 mL) and saturated aqueous NaHCO3 (7.5 mL) and stirred overnight at room temperature The solid was filtered, washed with water and hexanes then dried in an oven at 80° C. to give 2-bromo-3-chloro-5H-pyrrolo[2,3-b]pyrazine (1.64 g) as brown solid. LC-MS: 232 (M−H). This was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.I[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Br:1][C:2]1[C:3]([O:13][CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2ccc(O)c(Br)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2ccc(OC(C)C)c(Br)c2n1
Temperature: 70 °C

Procedure:
A mixture of 8-bromo-2-methylquinolin-7-ol (0.093 g, 0.39 mmol), 2-iodopropane (0.078 mL, 0.78 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in acetone (1.6 mL, 0.39 mmol) was heated at 70° C. for 12 hours. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification by normal phase chromatography on silica (10% ethyl acetate/hexanes) provided the title compound.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)[NH:2]2>C(OCC)(=O)C.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8](=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1)[NH:2]2
Reactant: COc1cc(CCCCC(=O)C2NC3C=CC2C3)cc(OC)c1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCCCC(=O)C2NC3CCC2C3)cc(OC)c1OC
Reaction time: 6 h
Yield: 99.4 %

Procedure:
A mixture of 85 mg of 1-(2-Aza-bicyclo[2.2.1]hept-5-en-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one and 50 mg of 10% Pd/C in 10 ml of ethyl acetate was hydrogenated at 50 psi for 6 hours. The reaction mixture was filtered and the solvent evaporated to yield 85 mg of 1-(2-Aza-bicyclo[2.2.1]hept-3-yl)-5-(3,4,5-trimethoxy-phenyl)-pentan-1-one as a mixture of exo and endo isomers. 1H NMR: (CDCl3) δ 6.40 (s, 2 H), 3.8 (s, 6 H), 3,75 (s, 3 H), 3.0-4.2 (m, 2 H), 2.5 (m, 5 H), 1.6 (m, 4 H), 1.4 (m, 1 H), 1.2 (m, 1 H). Mass spectrum m/e=348.2 (P+1).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][C:28](CO)=[CH:27][CH:26]=1>ClCCl>[Br:5][CH2:1][C:36]1[CH:37]=[CH:38][C:33]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:34][CH:35]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(-c2ccccc2)cc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
Carbon tetrabromide (8.99 g, 27.1 mmol) and triphenyl phosphine (7.11 g, 27.1 mmol) were added to a stirred solution of biphenyl-4-yl methanol (5.00 g, 27.1 mmol) in dichloromethane (100 mL) at room temperature. Stirring was continued at room temperature for 1.5 hours then the solvent removed by evaporation under reduced pressure. The residue was purified by column chromatography on silica gel (1:20 diethyl ether:cyclohexane) to give the title compound (6.37 g, 95%) as a white solid. 1H NMR (400 MHz: CDCl3): 7.6 (4 H), 7.45 (4 H), 7.35 (1 H), 4.55 (2 H).
Reaction SMILES: [C:1]([O:4]C1C=C(Cl)C(OC2C=CC(NC(=O)C)=C(Br)C=2)=C(Cl)C=1C)(=[O:3])[CH3:2].C(O[C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:47])[CH3:46])=[C:40]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:39]=2)=[C:32]([Cl:54])[C:31]=1C)(=O)C>>[Cl:36][C:34]1[CH:35]=[C:30]([CH2:2][C:1]([OH:4])=[O:3])[CH:31]=[C:32]([Cl:54])[C:33]=1[O:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][C:45](=[O:47])[CH3:46])=[C:40]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:39]=1
Reactant: CC(=O)Nc1ccc(Oc2c(Cl)cc(OC(C)=O)c(C)c2Cl)cc1Br
Reactant: CC(=O)Nc1ccc(Oc2c(Cl)cc(OC(C)=O)c(C)c2Cl)cc1-c1ccccc1
Product: CC(=O)Nc1ccc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)cc1-c1ccccc1
Yield: 66.4 %

Procedure:
Methyl[3,5-dichloro-4-(4-acetamido-3-bromophenoxy)phenyl] acetate (100 mg) was coupled with n-tributylphenyltin (140 mg, 0.38 mmol), using the same procedure as described in Example 3(a). This gave 70 mg (70%) of methyl(3,5-dichloro-4-[4-acetamido-3-phenylphenoxy]phenyl) acetate. A part of the obtained ester (50 mg) was hydrolysed using the method described in Example 1(i), to give 45 mg (95%) of 3,5-dichloro-4-(4-acetamido-3-phenylphenoxy)phenylacetic acid, m/z 430.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:8][O:7][CH2:6][C:5]([NH2:9])=[N:4][C@@:3]21[C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=1)[CH2:12][CH2:11][CH2:10]2.[C:21]([C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1)#[N:22]>>[NH2:9][C:5]1[CH2:6][O:7][CH2:8][C:2]([F:1])([F:20])[C@@:3]2([C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:29](=[O:30])[C:26]4[CH:25]=[CH:24][C:23]([C:21]#[N:22])=[CH:28][N:27]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCCc3ccc(N)cc32)C(F)(F)COC1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCC3)N=C(N)COCC2(F)F)nc1
Yield: 37 %

Procedure:
The condensation of (R)-6′,6′-difluoro-3,4,6′,7′-tetrahydro-2H,2′H-spiro[naphthalene-1,5′-[1,4]oxazepine]-3′,7-diamine (intermediate C4.1) and 5-cyanopicolinic acid yielded the title compound (37% yield) as an off-white solid. MS (ISP): m/z=412.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:19][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: NC1CCCCC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2c(NC3CCCCC3)nncc2c1
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 68.6 %

Procedure:
A mixture of 6-bromo-I-chlorophthalazine (Example 1, 0.245 g, 1 mmol), cyclohexanamine (0.22 g, 2 mmol) and potassium carbonate (0.14 g, 1 mmol) in 5 mL acetonitrile were added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After 20 min., all starting material was converted to product (M+1=306, 308). The mixture was concentrated under vacuum, and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2 M ammonia in MeOH/DCM to give (0.21 g) 6-bromo-N-cyclohexylphthalazin-1-amine as a yellow solid. Found MS (ES+): 306, 308(M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:11]=2[CH3:28])[CH2:4][O:3]1.C(N(CC)C(C)C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.C(=O)([O-])[OH:51].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1.[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Hf+4]>[CH3:1][C:2]1([CH3:29])[O:3][CH2:4][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:51])[C:11]=2[CH3:28])[CH2:6][O:7]1
Reactant: O=C([O-])O
Reactant: Cc1cnc(CSc2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Agent: [Hf+4]
Agent: CCCC[O-]
Agent: O=S([O-])([O-])=S
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
A mixture of 2-(((4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, 1.21 mmol) and N,N,N′,N′-(−)-tetramethyl-(D)-tartaramide (396 mg, 1.94 mmol) in toluene (4 ml) was dissolved by heating at 40° C. for 10 minutes in a nitrogen atmosphere. Hafnium tetrabutoxide (315 μL, 0.78 mmol) was added to the mixture and further stirred at the same temperature for one hour. After the reaction mixture was cooled to room temperature, N,N-diisopropylethylamine (90 μl, 0.52 mmol) was added and subsequently, cumene hydroperoxide (267 μl, 1.46 mmol as the content was regarded as 80%) was added dropwise to the mixture and then the mixture was stirred at room temperature for 22 hours. After a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium thiosulfate solution were added, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtrated, and concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 30 g, elution solvent: ethyl acetate, ethyl acetate/methanol 7:3, 1;1 gradient). The fractions containing the title compound were collected with ethyl acetate and concentrated to obtain the title compound (206 mg, yield: 40%) as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=3[CH3:26])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][C:17]=3[CH3:26])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:8]
Reactant: Cc1cc(C(F)(F)F)ccc1NC1CN(c2ncc(Cl)cc2C(=O)O)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(C(F)(F)F)cc4C)C3)CC2)cc1
Yield: 74.7 %

Procedure:
The title compound (D170) (43 mg) was prepared according to the experimental procedure described in Description 169 starting from 5-chloro-2-(3-((2-methyl-4-(trifluoromethyl)phenyl)amino)azetidin-1-yl)nicotinic acid (D119) (40 mg, 0.103 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (23.6 mg, 0.103 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]#[N:16])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)(C)C>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15](=[NH:16])[NH:19][OH:20])[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCC1CCN(C#N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)NO)CC1

Procedure:
(1-Cyano-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (2 g, 8.36 mmol), hydroxylamine hydrochloride (3.48 g, 50.14 mmol) and triethylamine (5.92 g, 58.5 mmol) were stirred in 30 ml of isopropanol at room temperature for 4 hours. The mixture was evaporated. After addition of water (pH4) and ethyl acetate, the organic layer was separated and evaporated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8](C2C=CC3C4CCNC5(CCCOC5)C=4OC=3C=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:29][CH:30]1[C:35]2([C:40]3[O:41][C:42]4[CH:47]=[C:46](I)[CH:45]=[CH:44][C:43]=4[C:39]=3[CH2:38][CH2:37][NH:36]2)[CH2:34][CH2:33][O:32][CH2:31]1.FC1C=C(S)C=CC=1>>[F:29][CH:30]1[C:35]2([C:40]3[O:41][C:42]4[CH:47]=[C:46]([S:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=5)(=[O:10])=[O:9])[CH:45]=[CH:44][C:43]=4[C:39]=3[CH2:38][CH2:37][NH:36]2)[CH2:34][CH2:33][O:32][CH2:31]1
Reactant: FC1COCCC12NCCc1c2oc2cc(I)ccc12
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Agent: Fc1cccc(S)c1
Product: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCOCC1F)NCC3

Procedure:
As described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3′-fluoro-7-iodo-2′,3,3′,4,5′,6′-hexahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,4′-pyran] and 3-fluorobenzenethiol The resulting diasteroisomeric mixture was separated using medium pressure liquid chromatography (140 g amine column) eluting with a gradient of EtOAc in hexanes (from 15% to 70% EtOAc).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[N:44]=[C:43]([N:45]([CH3:47])[CH3:46])[CH:42]=[CH:41][CH:40]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([N:45]([CH3:47])[CH3:46])[N:44]=2)[CH:27]=1)[C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CN(C)c1cccc(CCl)n1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccc(N(C)C)n3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 43.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.78 g) and 6-chloromethyl-2-(dimethylamino)pyridine (0.46 g) as starting materials, 5-benzyloxy-N-({1-[(6-dimethylaminopyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.43 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:19]O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c([N+](=O)[O-])c1C
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of 3,4-dimethyl-2-nitrobenzoic acid (13 g) and thionyl chloride (11.8 g) in toluene (100 ml) was refluxed for 4 h. The reaction mixture was cooled at 0° C., treated with methanol (15 ml) and the solvent was removed under vacuum. The reaction mixture was treated water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over sodium sulfate and concentrated to give methyl 3,4-dimethyl-2-nitrobenzoate (10 g). 1H-NMR (400 MHz, CDCl3): 2.19 (s, 3H), 2.38 (s, 3H), 3.87 (s, 3H), 7.25 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: C(O[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)C.CC([O-])(C)C.[K+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>C1COCC1.Cl>[I:11][C:7]1[CH:6]=[C:5]([C:4](=[O:12])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
Ethyl-3-iodobenzoate (25.4 g, 92.0 mmol) was dissolved in THF (60 mL) and cooled to 0° C. followed by the addition of KOt-Bu (20.6 g, 184 mmol). The mixture was stirred for 15 minutes followed by the addition of ethyl acetate (8.91 g, 101 mmol). The mixture was warmed to ambient temperature, stirred for 2 hours, diluted with aqueous HCl (10%, 200 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to provide the titled compound (29.3 g, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][CH:13]=[N:12][C:11]=2[CH:15]=1.[Na+].[I-].[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[S:14][CH:13]=[N:12][C:11]=3[CH:15]=2)[CH2:28][CH2:27]1
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Reactant: BrCCCCOc1ccc2scnc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Clc1cccc(C2CCN(CCCCOc3ccc4scnc4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
A mixture of intermediate 26 (114 mg, 0.4 mmol) and NaI (120 mg, 0.8 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 47 (160 mg, 0.6 mmol) and anhydrous K2CO3 (221 mg, 1.6 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred overnight. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 5-(4-(4-(2,3-dichlorophenyl)piperidin-1-yl)butoxy)benzo[d]thiazole (compound 21) (144 mg, 66%). 1H NMR (300 MHz, CDCl3): δ 8.97 (s, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.33-7.29 (m, 1H), 7.26-7.16 (m, 1H), 7.09 (dd, J=2.1 Hz, 8.7 Hz, 3H), 4.10 (t, J=6.6 Hz, 2H), 3.13-3.09 (m, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.14-2.10 (m, 2H), 1.91-1.74 (m, 10H). HPLC: 99%, RT 2.689 min. MS (ESI) m/z 435.3 [M+H]+. mp: 79-81° C.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28]>>[CH:1]1([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([C:27](=[O:28])[C:26]2[C:25]([Cl:24])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:34])[CH:12]=[C:11]3[C:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CN1CC=C(c2c[nH]c3ccc(OC4CCCCC4)cc23)CC1
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccc(OC4CCCCC4)cc23)CC1

Procedure:
(40.1 mg, 100%); from 5-cyclohexyloxy-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4c, 25.7 mg, 0.083 mmol) and 2,6-dichlorobenzoyl chloride (30 uL, 0.21 mmol); HRMS-FAB+ for C27H28N2O2Cl2 : calculated MH+ : 483.16061; found: 483.15611.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:10]([I:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21]>CCOCC>[I:17][C:10]1[C:9]([O:8][CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1cccc(O)c1I
Reactant: C=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(COc1cccc(C=O)c1I)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.72 g (0.28 mmol) of sodium hydride are dissolved in 660 ml of ether and 120 ml of dimethylformamide under argon, and 64.1 g (0.26 mol) of 3-hydroxy-2-iodobenzaldehyde in 65 ml of ether are slowly added. After the mixture has been stirred at room temperature for 15 minutes, 61 g (0.28 mol) of 3-bromo-2-phenyl-1-propene, dissolved in 60 ml of ether, are added dropwise and the mixture is stirred overnight.
Reaction SMILES: O.[Cl-:2].[OH:3][C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([C:12]#[C:13]/[C:14](/[CH3:36])=[CH:15]/[CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([CH3:37])[CH2:5]1.[H][H]>CO.OCCSCCSCCO>[Cl-:2].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([CH:12]=[CH:13][C:14]([CH3:36])=[CH:15][CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:6]([CH3:37])[CH2:5]1
Reactant: CC1=C(C#C/C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)C[C@H](O)C1
Reactant: [H][H]
Agent: OCCSCCSCCO
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CC(C=CC1=C(C)CC(O)CC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A suspension of 46.6 g of water-moist Raney-nickel and 518 mg of 1,2-bis(2-hydroxyethylthio)ethane in 1 l of methanol was pre-hydrogenated at 30° C. under normal pressure in a sulphonation flask provided with a gasification stirrer. Subsequently, a solution of 320 g of (4R,2E)-[5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium chloride in 2.1 l of methanol was added thereto and the mixture was hydrogenated at 40° C. and 1.1 bar of hydrogen. 15.6 l of hydrogen were taken up within 5 hours. The catalyst was filtered off and the filtrate was concentrated to a weight of 575 g. The product was crystallized by slowly pouring in 9.6 l of ethyl acetate. The suspension was stirred at room temperature for 2 hours and filtered. The crystals were washed with a small amount of methanol/ethyl acetate and dried at 60° C./0.01 mbar, there being obtained 272.2 g (84.7%) of [5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienyl]triphenylphosphonium chloride (containing 97% of the (4R,2E,4Z)-isomer and 2% of the (4R,2Z,4Z)-isomer in accordance with HPLC) of melting point 211°-212° C. and [α]D20 =-26.2° (c=1, chloroform).