Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([CH:18]=O)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21].Cl>O1CCCC1>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH:16](/[CH:18]=[CH:21]/[C:20]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethyl phosphonoacetate (1.9 mL; 9.72 mmol) was dissolved in tetrahydrofuran (30 mL). Potassium tert-butoxide (1.1 g; 9.72 mmol) was added portionwise. 3-Formylazetidine-1-car-boxylic acid tert-butyl ester (1.0 g; 5.40 mmol) was dissolved in tetrahydrofuran (6 mL) and added to the reaction mixture. The reaction mixture was stirred for 1 hour at room temperature. Ethyl acetate (100 mL) and hydrochloric acid (100 mL; 1 N) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×50 mL) and the combined organic phases were washed with saturated sodium hydrogen carbonate (100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×30 cm) using ethyl acetate/heptane (1:1) as eluent to afford 1.0 g of 3-((E)-2ethoxycarbonylvinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][C@H:15]3[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=5[N:32]=4)[CH2:17][N:16]3C(OC(C)(C)C)=O)[C:7]=2[CH:41]=1)#[N:2].Cl.O1CCOCC1>O1CCOCC1>[O:12]=[C:9]1[N:8]([CH2:13][CH2:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:27][CH2:28][C:29](=[O:33])[NH:30][C:31]=4[N:32]=3)[CH2:17][NH:16]2)[C:7]2[CH:41]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc3c(n2)NC(=O)CO3)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](NCc3ccc4c(n3)NC(=O)CO4)CN1)C(=O)CO2
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of tert-butyl (2R,5S)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidine-1-carboxylate (Intermediate 182, 0.138 g) in dioxane (2 mL) was added 4M HCl/dioxane (1 mL). After 1 hour at room temperature, the reaction was concentrated and evaporated twice from methanol. The solid was suspended in methanol and filtered to yield 73 mg of the name compound as a bis HCl salt.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2.N[C:23]1C=CC(C2CCC(=O)CC2)=C2[C:31]=1C(=O)N(C)C2.N1CCCC1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:21][CH2:31][CH2:23][CH2:20]3)[CH2:15][CH2:14]2)=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[CH2:7]2
Reactant: CN1Cc2c(C3CCC(N(C)C)CC3)ccc(N)c2C1=O
Reactant: CN1Cc2c(C3CCC(=O)CC3)ccc(N)c2C1=O
Solvent: C1CCNC1
Product: CN1Cc2c(C3CCC(N4CCCC4)CC3)ccc(N)c2C1=O

Procedure:
The title product was prepared according to the procedure for Compound 233A using 7-amino-2-methyl-4-(4-oxocyclohexyl)-2,3-dihydro-1H-isoindol-1-one and pyrrolidine. Product used crude in the next step.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:24]=[C:23](Cl)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1](=[N:14][C:15]1[CH:24]=[C:23]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:22]2[C:17](=[CH:18][C:19]([S:26][C:27]3[CH:28]=[C:29]([C:33]4([C:39]#[N:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:30]=[CH:31][CH:32]=3)=[CH:20][CH:21]=2)[N:16]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccccc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Temperature: 90 °C

Procedure:
1r (100 mg, 0.18 mmol), phenylboronic acid (26 mg, 0.21 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), and potassium carbonate (50 mg, 0.36 mmol) was dissolved in 1,4-dioxane and water and degassed with N2. The mixture was heated to 90° C. until no starting material was seen by tlc analysis. The reaction was cooled to room temperature, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the desired product, 1s.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]([NH2:12])[CH3:11])[C:4]=2[O:3][CH2:2]1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]([NH:12][C:42]([C:38]3[CH:37]=[C:36]4[C:41](=[CH:40][CH:39]=3)[N:33]([CH2:32][C:29]3[CH:28]=[CH:27][C:26]([C:21]5[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:31][CH:30]=3)[C:34]([CH3:46])=[C:35]4[CH3:45])=[O:43])[CH3:11])[C:4]=2[O:3][CH2:2]1
Reactant: C[C@H](N)c1cccc2c1OCO2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc4c3OCO4)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using (S)-1-(benzo[d][1,3]dioxol-4-yl)ethanamine and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 547 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:7]=[C:6]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)[C:5]=1[N+:18]([O-:20])=[O:19])[CH3:2]
Reactant: CCOc1nc(SC)nc(N2CCSCC2)c1[N+](=O)[O-]
Reactant: C1CNCCN1
Product: CCOc1nc(N2CCNCC2)nc(N2CCSCC2)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
23 gm (0.07 mol) of 6-ethoxy-2-methylthio-5-nitro-4-thiomorpholino-pyrimidine were added to 68 gm (0.8 mol) of molten piperazine, and the mixture was heated at 110°C for 1 hour. After cooling, ice water was added to the reaction mixture, and the yellow precipitate formed thereby was suction-filtered off, washed with water and recrystallized from isopropanol. Yield: 18 gm (70% of theory); m.p. 166.5°-168.5°C
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([CH3:36])[C:34]=1[NH2:35])[O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:31])[CH2:14][CH2:13]2)[CH:7]=1.[CH:37]1([CH2:40][C:41](O)=O)[CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(O)(=O)C>CN(C=O)C>[CH:37]1([CH2:40][C:41]2[NH:1][C:2]3[CH:3]=[C:4]([O:5][C:6]4[N:11]=[CH:10][N:9]=[C:8]([N:12]5[CH2:13][CH2:14][CH:15]([N:18]6[CH2:24][CH2:23][C:22]7[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:21]=7[NH:20][C:19]6=[O:31])[CH2:16][CH2:17]5)[CH:7]=4)[CH:32]=[C:33]([CH3:36])[C:34]=3[N:35]=2)[CH2:39][CH2:38]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c(N)c(N)c4)ncn3)CC1)C(=O)N2
Reactant: O=C(O)CC1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5nc(CC6CC6)[nH]c5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.20 g (0.42 mmol) 3-{1-[6-(3,4-diamino-5-methyl-phenoxy)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one, 46 mg (0.46 mmol) cyclopropyl-acetic acid, 151 mg (0.47 mmol) TBTU and 0.14 mL (1.00 mmol) TEA in 2.00 mL DMF were stirred for 4 h at RT. Then 2.00 mL glacial acetic acid was added and the mixture was stirred overnight at RT. In addition the reaction mixture was stirred for 1 h at 100° C., then cooled and purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18].CN(C=O)C>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)cn1
Temperature: 80 °C
Yield: 84.8 %

Procedure:
A flask charged with 1H-imidazole-4-carboxylic acid methyl ester (0.29 g, 2.3 mmol), K2CO3 (0.60 g, 4.3 mmol), SEM-Cl (0.45 mL, 2.5 mmol) and DMF (5 mL) was heated for 12 h at 80° C. The reaction was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4 and concentrated. The residue was purified by elution from a 20-g SPE cartridge (silica) with 5% MeOH/DCM to give 0.50 g (85%) of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester. This compound was stirred overnight at RT in MeOH (3.0 mL) and 1N NaOH (1.9 mL) and then concentrated to give 0.43 g (70%) of the title compound as a white solid. Mass spectrum (ESI), m/z): Calcd. for C10H18N2O3Si, 243.1 (M+H), found 243.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C1C=CC=CC=1)(=O)=O)[CH:7]=[CH:6]2)#[N:2].[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)#[CH:24]>CCCCCCC.CCOC(C)=O>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]#[C:24][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11]3)=[CH:26][CH:27]=1
Reactant: N#Cc1ccc2cc(OS(=O)(=O)c3ccccc3)ccc2c1
Reactant: C#Cc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(C#Cc2ccc3cc(C#N)ccc3c2)cc1

Procedure:
This product was prepared from benzenesulfonic acid 6-cyano-naphthalen-2-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 95:5; yield (140 mg, 98%); 1H NMR δ (CDCl3): 8.20 (s, 1H), 8.06 (s, 1H), 7.88 (t, J=7.81 Hz, 2H), 7.71-7.59 (dm, 2H), 6.92 (m, 2H), 3.83 (s, 3H); LCMS m/z: 283.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)([OH:11])[CH3:10].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[CH2:18][Cl:17])=[C:3]([C:9]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)([OH:11])[CH3:10])[CH:4]=1
Reactant: CC(O)(c1ccco1)c1cc(Br)ccc1N
Reactant: O=C(Cl)CCl
Product: CC(O)(c1ccco1)c1cc(Br)ccc1NC(=O)CCl

Procedure:
Prepared from 1-(2-amino-5-bromophenyl)-1-(2-furyl)ethanol and chloroacetyl chloride generally according to the procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.84 (s, 1H), 8.07 (d, J=8.76 Hz, 1H), 7.57 (bs, 1H), 7.50 (dd, J=2.33, 8.76 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J=2.31 Hz, 1H), 6.46-6.42 (m, 2H), 4.35 (d, J=1.69 Hz, 2H), 1.85 (s, 3H); MS (ES) m/z 356/358 ([M−H]−, 100%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: Cc1nc[nH]n1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncn(-c2c(F)cc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 18.1 %

Procedure:
Step R (1): A mixture of 3-methyl-1H-1,2,4-triazole (8.12 g, 98 mmol), 1,2,3-trifluoro-5-nitrobenzene (17.3 g, 98 mmol), and sodium bicarbonate (8.21 g, 98 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford a 1.7:1.0 mixture of two regioisomeric products as an orange solid. The orange solid was recrystallized from EtOAc (hot-cold) to provide 4.25 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole as a white solid. The mother liquor was recrystallized from EtOAc/Hex (hot-rt) to afford 1.89 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole as a light yellow solid. The mother liquor was repeatly chromatographed under the previously stated conditions to provide two samples. One sample was partially enriched in the slightly less polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole. The other sample was partially enriched in the slightly more polar isomer, 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. Both samples were independently recrystallized from EtOAc/Hex to provide an additional 1.9 g of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 1.37 g of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole. A combined total of 6.15 g (26% yield) of 1-(2,6-difluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole and 3.2 g (13% yield) of 1-(2,6-difluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=O)[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.S(Cl)([Cl:24])=O>>[CH3:1][N:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH2:18][C:19]([Cl:24])=[O:21])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: CN1Cc2ccccc2C(c2cccc(CC(=O)O)c2)C1
Reactant: O=S(Cl)Cl
Product: CN1Cc2ccccc2C(c2cccc(CC(=O)Cl)c2)C1

Procedure:
3.4 g (10.7 mmol) of 3-[2-methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenylacetic acid are treated with 17.6 ml of thionyl chloride with stirring. The mixture is refluxed for one hour. The mixture is then evaporated to dryness. 3-[2-Methyl-1,2,3,4-tetrahydro-4-(R,S)-isoquinolinyl]phenylacetyl chloride is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16](O)[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([Cl:27])[C:15]3[C:10](=[C:11]([O:23][CH3:24])[C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(O)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC
Product: COc1cc2c(Cl)nc(-c3ccc(Cl)cc3)nc2c(OC)c1OC

Procedure:
18.2 g of 2-(4-chlorophenyl)-hydroxy-6,7,8-trimethoxyquinazoline were heated at 100° C. for 3 h in 120 ml of phosphorus oxychloride. The excess phosphorus oxychloride was distilled off and the oily residue was stirred with ice water. The solid was filtered off with suction and dried under reduced pressure. Yield: 15.0 g. M.p.: 159° C.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][N:10](C)[C:11]2=[O:14])=[CH:6][CH:5]=1.O>C(O)(=O)C>[Br:1][C:8]1[C:7]2[C:12](=[CH:13][C:4]([F:3])=[CH:5][CH:6]=2)[C:11](=[O:14])[NH:10][CH:9]=1
Reactant: Cn1ccc2ccc(F)cc2c1=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]cc(Br)c2ccc(F)cc12
Temperature: 26 °C
Reaction time: 2 h
Yield: 25.8 %

Procedure:
Bromine (3.8 g, 24 mmol) in acetic acid (6 mL) was added slowly to a mixture of 7-fluoro-2-methylisoquinolin-1-one (4 g, 22.4 mmol) in acetic acid (8 mL) at 0° C. After stirring at 26° C. for 2 h, the mixture was poured into water (100 mL) and the solid was collected by filtration. Purification by silica gel chromatography (PE:EA=20:1) gave the title compound (1.4 g, 44%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=9.2 Hz, 1H), 7.84 (dd, J1=9.6 Hz, J2=4.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.34 (s, 1H), 3.62 (3H, s). LCMS: 255.9 [M+H]+
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([OH:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20]Cl>CN(C)C=O>[C:1]1([N:7]2[C:11]([Cl:20])=[N:10][C:9]([OH:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ncn(-c2ccccc2)n1
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1nc(Cl)n(-c2ccccc2)n1

Procedure:
32.2 g of 1-phenyl-3-hydroxy-1,2,4-triazole and 40.5 g of triethylamine in 300 ml of dimethyl formamide. While cooling with ice, 21.3 g of chlorine gas are passed in at 20° to 30°C. Subsequently the resulting triethylamine hydrochloride is filtered off and the solvent is distilled off in vacuo. The residue is taken up in 300 ml of water and extracted 4 times with 200 ml of ether. The combined ethereal extracts are dried over sodium sulphate and, after the solvent has been filtered off, concentrated in vacuo. The residue is recrystallised from acetonitrile. Yield: 15.0 g (38.4 % of theory); m.p. 146°-147°C.
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:17].Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=1)(=[O:21])=[O:20]>C1COCC1>[C:9]([C:5]1[CH:4]=[C:3]([I:17])[C:2]([O:1][S:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=2)(=[O:21])=[O:20])=[C:7]([I:8])[CH:6]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1ccccc1)c1cc(I)c(O)c(I)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(I)c(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)c(I)c1
Yield: 30 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using (4-hydroxy-3,5-diiodo-phenyl)-phenyl-methanone (0.346 g, 0.768 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.928 g, 3.92 mmol) in THF. Purification On Biotage KP-Sil, eluting with 10% MeOH/CHCl3 followed by crystallization from EtOAc/hexane gave 0.15 g (30%) of the title compound as an orange solid, mp 190° C. 1H NMR (DMSO-d6) δ 7.22-7.35 (m, 2H), 7.58 (t, 2H), 7.69-7.75 (m, 3H), 7.95 (d, 1H), 8.10 (s, 2H). IR (KBr) 3400, 3100, 1660, 1280 and 1180 cm-1. mass spectrum (+FAB) m/z 651 (M+H). Anal. Calcd. for C20H12I2O7S 0.5H2O: C,36.44; H,1.99; N,0.00. Found: C,36.50; H,2.16; N,0.09.
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)(=O)OC.[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH:36]=O>C1COCC1>[CH3:20][O:21][C:22](=[O:38])[CH2:23][O:24][CH2:25][C:26]#[C:27][CH2:28][N:29]1[C:34](=[O:35])[CH2:33][CH2:32][CH2:31][C@@H:30]1/[CH:36]=[CH:9]/[C:10](=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1
Reactant: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 15 mg, 0.39 mmol) was added to a solution of [3-(3-chlorophenyl)-2-oxopropyl]-phosphonic acid dimethyl ester (97 mg, 0.35 mmol) in THF (1.5 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (0.37 mmol, crude) in THF (1.5 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 15 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20% →30% EtOAc/CH2Cl2, gradient) afforded 100 mg (68%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH2:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17]>C(N(CC)CC)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Cc1ccc(CN)o1
Solvent: CCN(CC)CC
Product: Cc1ccc(CNc2ccccc2[N+](=O)[O-])o1
Yield: 89 %

Procedure:
A mixture of 40 parts of 5-methyl-2-furanmethanamine, 46 parts of 1-chloro-2-nitrobenzene and 210 parts of N,N-diethylethanamine was stirred and refluxed for 2 days. The reaction mixture was evaporated, water was added and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using trichloromethane as eluent. The filtrate was evaporated, yielding 62 parts (89%) of 5-methyl-N-(2-nitrophenyl)-2-furanmethanamine as a residue (intermediate 2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(O)C.C(O)(=O)C.O=[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Fc1ccc2[nH]cc(Cc3ccncc3)c2c1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CC(=O)O
Product: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reaction time: 48 h

Procedure:
A mixture of 5-fluoro-3-(4-pyridinylmethyl)-1H-indole (4.50 g, 20 mmol) and PtO2 (0.50 g, 2.2 mmol) in ethanol and acetic acid is hydrogenated under 45 psi at room temperature for 48 hr. After filtration of the catalyst and concentration of the filtrate, the residue is taken up with water, basified to pH 11 with 1N NaOH and extracted with CH2Cl2/iPrOH (3/1). The combined extracts are dried over Na2SO4 and concentrated in vacuo to give a pink solid. The solid is crystallized from EtOAc to afford the title compound as a white solid, 4.0 g (86%) mp 155-157° C. (Lit. mp 163° C., Malleron et al, J. Med. Chem. 1193,36,1194).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>>[CH3:9][C:4]1[N:3]=[C:2]2[NH:1][C:10](=[O:11])[O:8][C:7]2=[CH:6][CH:5]=1
Reactant: Cc1ccc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: Cc1ccc2oc(=O)[nH]c2n1

Procedure:
Reaction of 2-amino-6-methylpyridin-3-ol with CDI (carbonyldiimidazole) in a corresponding manner to Example 1.2 gives the desired product; ESI: 151 (M+H), Rt=1.58 min (method B).