Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[CH:4][C:3]1=2.[CH3:22]C1C(C#C)=CC2C(C)(C)CCC(C)(C)C=2C=1.COC(Cl)=O.C([Li])CCC>>[CH3:22][C:5]1[C:6]([C:14]#[C:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:21])([CH3:1])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)C#Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: COC(=O)Cl
Agent: [Li]CCCC
Product: CCOC(=O)C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C

Procedure:
Employing the same general procedure as used for the preparation of ethyl 3-[5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl]propiolate (Compound A), but instead using 1.9 g of (3-methyl-5,5,8,8,-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethyne, 940 mgs (10 mmols) of methylchloroformate and 8.8 mmols of n-butyllithium the title compound was obtained as an oil.
Reaction SMILES: ClCCl.[C:4]([Si:8]([CH3:24])([CH3:23])[O:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@H:16]([C:18]([S:20][CH3:21])=[S:19])[CH3:17])[NH:14][C:13]1=[O:22])[CH3:11])([CH3:7])([CH3:6])[CH3:5].[Si](O[C@@H]([C@@H]1[C@@H]([C@@H](C(SC)=S)C)NC1=O)C)(C(C)(C)C)(C)C.Cl[C:47](=[O:54])[C:48]([O:50][CH2:51][CH:52]=[CH2:53])=[O:49]>C(N(CC)CC)C>[CH2:51]([O:50][C:48](=[O:49])[C:47]([N:14]1[C@H:15]([C@H:16]([C:18]([S:20][CH3:21])=[S:19])[CH3:17])[C@@H:12]([C@H:10]([O:9][Si:8]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:23])[CH3:24])[CH3:11])[C:13]1=[O:22])=[O:54])[CH:52]=[CH2:53]
Reactant: CSC(=S)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)C(=O)Cl
Agent: CSC(=S)[C@@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=S)SC
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a mixture of dichloromethane (32.6 mg) and a mixture (33.1 mg) of (3S,4S)-3-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine were added triethylamine (30.4 mg) and allyl chloroglyoxylate (32.6 mg) successively at 0° C. After stirring for 10 minutes at the same temperature, the solution was washed with water, 1N hydrochloric acid, brine, and dried. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (5% diethyl ether-hexane) to afford a mixture (23 mg) of (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine and (3S,4S)-1-(allyloxyoxalyl)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1S)-1-{(methylthio)thiocarbonyl}ethyl]-2-oxoazetidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1.[CH2:35]([OH:38])[CH2:36][OH:37]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[OH:37][CH2:36][CH2:35][O:38][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:17])=[O:16])[C:3]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1
Reactant: OCCO
Reactant: COc1cccc(Oc2c(Cl)nc(N3CCOCC3)nc2NS(=O)(=O)CCc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: COc1cccc(Oc2c(NS(=O)(=O)CCc3ccccc3)nc(N3CCOCC3)nc2OCCO)c1
Temperature: 100 °C
Reaction time: 288 h

Procedure:
A suspension of 2-phenyl-ethanesulfonic acid [6-chloro-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.27 g) in ethylene glycol (12 ml) was treated with K-tert.-butylate (2.82 g). The resulting solution was stirred at 100° C. for 12 d. The solution was cooled to rt, diluted with 10% aq. citric acid (150 ml) and extracted twice with EA (150 ml). The organic phase was washed with water (50 ml) and evaporated. The crude product was purified by chromatography on silica gel eluting with heptane:EA 1:1 to 1:2 to furnish 2phenyl-ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(3-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl]-amide (1.1 g) as a white solid. LC-MS: tR=4.66 min, [M+1]+=531.20, [M−1]−=529.14.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.C(Cl)(Cl)Cl>CN(C)C=O.[Cu]>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(I)cc1OC
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(C(=O)OC)c(OC)c2)cc1OC
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a mechanically stirred suspension of 90 g of copper powder in 450 mL of dimethylformamide was added 90 g of methyl 4-iodo-2-methoxybenzoate (which was prepared as in Example 1). The resulting mixture was heated at reflux for 6 days and then cooled to room temperature and diluted into 1500 mL of chloroform. The mixture was filtered and the copper was washed with 2×150 mL of chloroform. The residual copper was suspended in 2 liters of water and extracted with 6×150 mL of chloroform. All the organic fractions were combined, dried and concentrated to approximately 250 mL. The concentrate was cooled to 0° C. and the precipitate filtered to give 33 g of 3,3'-dimethoxy-4,4'-bis(methoxycarbonyl)biphenyl as a pale yellow powder. Deprotection of the dimethoxy compound was accomplished with boron trichloride according to step 5 of Example 1 to yield 3,3'-dihydroxy-4,4'-bis(methoxycarbonyl)biphenyl. The structure was confirmed by NMR.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[S:9][CH3:10].[CH3:11]O>C([O-])([O-])=O.[K+].[K+]>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([S:9][CH3:10])=[N:4][CH:5]=1)#[CH:11]
Reactant: CO
Reactant: CSc1ncc(C=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cnc(SC)n1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 72 %

Procedure:
To a mixture of 850 mg (5.44 mmol) of 3-methyl-2-methylsulfanyl-3H-imidazole-4-carbaldehyde and 1.34 g (7.00 mmol) of dimethyl 2-oxo-1-diazopropylphosphinate in 15 mL of MeOH was added 1.52 g (11.0 mmol) of K2CO3. The mixture was stirred at room temperature for 28 hours. The mixture was diluted with saturated K2CO3 (10 mL) and and extracted with CH2Cl2 (3×75 mL). The combined extracts were dried over MgSO4, concentrated, and chromatographed (0 to 100% EtOAc in hexanes) to give the 5-ethynyl-1-methyl-2-methylsulfanyl-1H-imidazole (600 mg, 72%) as a colorless liquid.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[Cl:22][CH2:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([CH2:23][Cl:22])[CH:25]=1
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.8 %

Procedure:
Triethylamine (1.93 mL; 13.78 mmol) was added at 0° C. to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (1.3 g; 5.51 mmol) and 3-(chloromethyl)benzoyl chloride (1.13 g; 5.79 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 1.45 g (76%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][NH:8][C:7](=S)[C:6]1=[O:13].[C:22]([NH:30][NH2:31])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>C(O)CCC>[Cl:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:30][N:31]=[C:7]2[C:6]1=[O:13]
Reactant: C[C@H]1CNC(=S)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Reactant: NNC(=O)c1cccnc1
Solvent: CCCCO
Product: C[C@H]1Cn2c(nnc2-c2cccnc2)C(=O)N1Cc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (S)-1-(2-chloro-3-(trifluoromethyl)benzyl)-6-methyl-3-thioxopiperazin-2-one (105 mg, 0.31 mmol) and nicotinohydrazide (47 mg, 0.34 mmol) in 1-butanol (3.1 mL) was heated at 130° C. for 16 h. After cooling to rt, the solvent was removed in vacuo. Purification by chromatography (SiO2; 0-20% IPA/EtOAc) afforded the desired product as a white solid (102 mg, 78%). MS (ESI): mass calcd. for C19H15ClF3N5O, 421.1; m/z found, 422.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.90 (d, J=1.8 Hz, 1H), 8.74 (dd, J=4.8, 1.4 Hz, 1H), 8.16-8.12 (m, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.48 (dd, J=7.9, 4.9 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 5.35 (d, J=15.6 Hz, 1H), 4.68 (dd, J=12.9, 4.5 Hz, 1H), 4.57 (d, J=15.6 Hz, 1H), 4.25 (dd, J=12.9, 1.8 Hz, 1H), 4.19-4.09 (m, 1H), 1.30 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[N:32][C:33]=3[NH2:35])[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[N:27]=2)=[CH:22][C:21]=1[O:49][CH3:50]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[NH2:35][C:33]1[N:32]=[CH:31][N:30]=[C:29]2[N:28]([C@H:36]3[CH2:41][CH2:40][C@H:39]([N:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)[CH2:38][CH2:37]3)[N:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([NH:19][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[O:12])=[C:21]([O:49][CH3:50])[CH:22]=3)[C:34]=12
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2[nH]1
Reaction time: 8 h

Procedure:
To 1H-2-indolecarboxylic acid (0.738 g, 4.58 mmol) in dichloromethane (14 mL) was added oxalyl chloride (4 mL, 45.8 mmol) and DMF (1 drop). The reaction mixture was stirred overnight. Solvent was evaporated and the residue was dissolved in Dichloromethane (5 mL). Half of the dichloromethane solution (2.5 mL) was added to a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.50 g, 1.145 mmol) in pyridine (6 mL) at 0° C. After 30 minutes, the solid as collected by filtration. Water was then added to the solid and the pH of the solution was adjusted to 10 with sodium hydroxide (1.0N). The aqueous was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1H-2-indolecarboxamide (0.312 g, 47%). 1H NMR (DMSO-d6) δ 1.49 (m, 2H), 2.05 (m, 6H), 2.15 (s, 3H), 2.32 (m, 5H), 2.51 (m, 4H), 3.97 (s, 3H), 4.66 (m, 1H), 7.10 (m, 1H), 7.22 (m, 1H), 7.30 (d, J=7.98 Hz, 1H), 8.11 (d, J=8.14 Hz, 1H), 8.24 (s, 1H), 9.44 (s, 1H).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:4][N:3]=1.CN1C(C2C=CC=CC=2)=NN=C1.[C:26]([C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][OH:45])[CH2:38][CH2:37]2)[CH:33]=[C:32]([C:46]([F:49])([F:48])[F:47])[N:31]=1)([CH3:29])([CH3:28])[CH3:27].ClCCCO.[H-].[Na+]>CN(C=O)C>[C:26]([C:30]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][CH2:44][O:45][C:2]3[N:6]([CH3:7])[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)=[N:4][N:3]=3)[CH2:38][CH2:37]2)[CH:33]=[C:32]([C:46]([F:48])([F:49])[F:47])[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1nc(N2CCN(CCCO)CC2)cc(C(F)(F)F)n1
Reactant: Cn1c(I)nnc1-c1ccccc1
Agent: Cn1cnnc1-c1ccccc1
Agent: OCCCCl
Agent: [H-]
Solvent: CN(C)C=O
Product: Cn1c(OCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)nnc1-c1ccccc1
Temperature: 0 °C

Procedure:
855 mg (3mmol) of 3-iodo-4-methyl-5-phenyl-1,2,4-(4H)-triazole (prepared by iodinating 4-methyl-5-phenyl-1,2,4-(4H)-triazole by a method similar to Izv. Akad. Nauk SSSR, Ser. Khim (1975), 616-619), were stirred, at 60° C. for 6 h, with 1.04 g (3 mmol) of 2-t-butyl-4-[4-(3-hydroxypropyl)piperazin-1-yl]-6-trifluoromethyl pyrimidine (prepared, by a method similar to Example 1, A.3, by reacting the product obtained as described in Example 1, A.2 with 3-chloropropanol) and sodium hydride in DMF. For the working-up, ice water was added to the mixture and the whole was extracted several times with methyl t-butyl ether. The residue which was obtained after drying with sodium sulfate and removing the solvent was purified by column chromatography (silica gel, methylene chloride/methanol). Yield, 140 mg (9% of theory) of oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:39])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[O:13])[S:10][CH:11]=1.NN>C1COCC1.CO>[NH2:17][CH2:16][C@@H:15]([NH:14][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH3:39])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]
Reactant: Cn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(Cl)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (150 mg, 0.262 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (123 uL, 2.62 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][C@H:9]([CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7][C:6]([OH:17])=[O:5]
Reactant: CC(C)CCC[C@@H](C)CCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)CCC(=O)O
Reaction time: 8 h

Procedure:
(4R)-4,8-dimethyl nonanoic acid t-butyl ester in 25 mL CH2Cl2 at 0° C. was treated with TFA (6 mL). The mixture was allowed to reach ambient temperature and stir overnight. The solvent was removed by rotary evaporation, and the mixture was purified by silica gel chromatography (95/5 hexane/EtOAc) to give 0.962 g (4R)-4,8-dimethyl nonanoic acid. m/z 185 (M−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:10]=[C:11]([NH:15]C(C2C=CN3C=2CSC3C2C=NC=CC=2)=O)[CH:12]=[CH:13][CH:14]=1)=[O:8].[N+](C1C=C(C=CC=1)C(C1C=CC=CN=1)=O)([O-])=O.Cl>C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:8]
Reactant: O=C(c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1)c1ccccn1
Agent: Cl
Agent: O=C(c1cccc([N+](=O)[O-])c1)c1ccccn1
Solvent: CCO
Product: Nc1cccc(C(=O)c2ccccn2)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
The 2-(3-aminobenzoyl)pyridine may be prepared as follows: Stannous chloride in the dihydrate form (63 g) is added, at a temperature in the vicinity of 3° C., to a suspension of 2-(3-nitrobenzoyl)pyridine (19 g) in a 3.7N solution (360 cc) of hydrogen chloride in ethanol, in the course of 45 minutes. The suspension obtained is stirred at a temperature in the vicinity of 4° C. for 1 hour and 30 minutes, at a temperature in the vicinity of 20° C. for 1 hour and 30 minutes and then at a temperature in the vicinity of 80° C. for 1 hour and 30 minutes. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is taken up with distilled water (200 cc). The aqueous solution is adjusted to a pH in the region of 11 by adding an aqueous 10N sodium hydroxide solution at a temperature in the vicinity of 25° C., saturated with sodium chloride and then extracted 3 times with diethyl ether (600 cc in total). The ether extracts are combined, washed 3 times with a saturated aqueous sodium chloride solution (300 cc in total), dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 40° C. A crude product (15.8 g) is obtained, which is chromatographed on an 8 cm diameter column containing silica (0.02-0.045 mm; 500 g). Elution is carried out with a mixture of cyclohexane and ethyl acetate (50:50 by volume) at a pressure of 0.4 bar (40 kPa), collecting 400 cc fractions. The first 7 fractions are discarded. The following 7 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. 2-(3-Aminobenzoyl) pyridine (12 g) in the form of a red oil is thereby obtained and it is used in the subsequent syntheses.
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[C:7]([N:6]1[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][O:27][CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc(N2CCOCC2)cc1

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and (4-morpholinophenyl)boronic acid and by reaction and purification in the same manner as in the method described in Example 43, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[C:6]1([C:2]([C:3]([Cl:16])=[O:4])([F:12])[F:1])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(F)(F)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(F)(F)c1ccccc1
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a flask charged with 2,2-difluoro-2-phenylacetic acid (0.8 g, 5.06 mmol), as prepared in the preceding step, under argon in an ice-bath was added oxalyl chloride (5 mL), and the reaction mixture stirred for 15 min. A solution of dimethylformamide (DMF) (37 mg, 0.506 mmol) in DCM (0.5 mL) was added. After 2 hours, the ice-bath was removed, and the mixture continued to stir for 1 hour. The solvents were evaporated, DCM was added, and then evaporated in vacuo giving the title compound (0.88 g, 98% yield), that was used immediately without further purification.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:23][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[C:16]([Cl:21])[C:15]([CH3:22])=[N:14]3)=O)(C)(C)C.CC(OC)(C)C>CC(O)=O>[ClH:21].[Cl:21][C:16]1[C:15]([CH3:22])=[N:14][C:13]2[N:18]([N:19]=[C:11]3[CH2:10][NH:9][CH2:23][C:12]3=2)[C:17]=1[CH3:20]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1nc2c3c(nn2c(C)c1Cl)CNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 199.4 %

Procedure:
Aq. 32% HCl (1.14 mL; 11.62 mmol; 3 eq.) was added to a suspension of 6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (1.25 g; 3.87 mmol; 1 eq.) in AcOH (6.25 mL) and the resulting mixture was stirred at room temperature for 2 hours then poured into MTBE (40 mL). The precipitate was filtered off, washed with MTBE (3×) and dried to afford the title compound (1 g, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ 10.55 (s, 2H), 4.57-4.52 (m, 4H), 2.83 (s, 3H), 2.61 (s, 3H). HPLC (max plot) 100.0%; Rt 1.38 min. UPLC/MS: (MS+) 222.9 ([M+H]+).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH3:18])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[CH3:18])[CH2:9][NH:8][CH2:16]2
Reactant: Cc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: Cc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3 (e) from 5-chloro-6-methyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Grey solid. MS (m/e): 170.1 ({37Cl}M+H+, 35%), 168.3 ({35Cl}M+H+, 100%).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:10][CH2:9]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[ClH:1].[ClH:1].[F:2][C:3]1[CH:33]=[CH:32][CH:31]=[CH:30][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(CCC(=O)N2CCN(CCOc3ccccc3F)CC2)cc(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(CCCN2CCN(CCOc3ccccc3F)CC2)cc(OC)c1OC
Yield: 173.7 %

Procedure:
To a solution of 1-{4-[2-(2-fluorophenoxy)ethyl]piperazin-1-yl}-3-(3,4,5-trimethoxyphenyl)-propan-1-one hydrochloride (0.2 g, 0.41 mmol) in THF (50 mL) was added LiAlH4 (0.2 g, 5 mmol). The reaction mixture was stirred under N2 for a day, cooled with an ice bath, and quenched with water (0.2 mL) and 10N NaOH aqueous solution (0.2 mL). The solid was filtered and the filtrate was concentrated to dryness. The residue was treated with ether and 2N HCl in ether (2 mL). The white solid was filtered and dried under vacuum to yield the title compound (0.18 g, 87%).
Reaction SMILES: ClC1C=CC(OCC(C2C=CC=CC=2)=O)=CC=1.[Cl:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][CH2:24]/[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26]\[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][CH2:24]/[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:38][CH:39]=1
Reactant: CCOC(=O)/C=C(\COc1ccc(Cl)cc1)c1ccccc1
Agent: O=C(COc1ccc(Cl)cc1)c1ccccc1
Product: CCOC(=O)/C=C(/COc1ccc(Cl)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 2-(4-chlorophenoxy)-1-phenylethanone, (Z)-ethyl 4-(4-chlorophenoxy)-3-phenylbut-2-enoate and (E)-ethyl 4-(4-chlorophenoxy)-3-phenylbut-2-enoate were obtained as colourless oils.