Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([N:41]3[CH2:40][CH2:39][N:38]([S:35]([C:30]4[CH:29]=[CH:28][C:27]5[C:32](=[CH:33][CH:34]=[C:25]([Cl:24])[CH:26]=5)[CH:31]=4)(=[O:37])=[O:36])[CH2:43][CH2:42]3)=[O:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)O)cc2)C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2)C1

Procedure:
In the same manner as in Referential Example 12, a reaction was conducted using 4-[[(3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl]oxy]benzoic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O1CCCC1.C([Li])CCC.[CH2:20]1[CH2:30][CH2:29][C:23](=[C:24]2[CH:28]=[CH:27][CH:26]=[CH:25]2)[CH2:22][CH2:21]1>O>[CH:24]1([C:23]2([CH:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)[CH2:29][CH2:30][CH2:20][CH2:21][CH2:22]2)[CH:25]=[CH:26][CH:27]=[CH:28]1
Reactant: C1=Cc2ccccc2C1
Reactant: C1=CC(=C2CCCCC2)C=C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: C1=CC(C2(C3C=Cc4ccccc43)CCCCC2)C=C1
Reaction time: 3 h
Yield: 68.8 %

Procedure:
Indene (5.8 g, 50 mmole) was placed in a 250 ml round bottom flask with 50 ml of THF (tetrahydrofuran). 34.3 ml (1.6 M, 55 mmole) of n-butyl lithium (n-BuLi) was added into the solution under an ice bath. The mixture turned orange red. The ice bath was removed and the mixture was stirred for 3 hours. 6.7 g of 6,6-pentamethylenefulvene (46 mmole) was added gradually to the mixture. After stirring for 24 hours, 1 ml of water was added to the mixture to terminate the reaction. The reaction mixture was stripped under vacuum to remove solvent, washed with 100 ml of pentane, and filtered to remove the salt. The crude product (i.e., filtrate) was purified by column chromatography (the packing was 20 g of silica gel, the eluent was 100% pentane). The solution was then concentrated under reduced pressure to obtain a pale yellow liquid (8.3 g, yield=69%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].C(=O)([O-])[O-].[Ca+2].Br[CH:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=O.Cl>CC(O)C>[C:20]1([C:18]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[S:10][C:17]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC(=S)c1ccccn1
Reactant: O=C(c1cccc2ccccc12)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)O
Product: c1ccc(-c2sc(-c3ccccn3)nc2-c2cccc3ccccc23)cc1

Procedure:
A 183 mg portion of pyridine-2-carbothioamide hydrochloride and 209 mg of calcium carbonate were added at room temperature to a 2-propanol solution (20 ml) of 340 mg of 2-bromo-1-(1-naphthyl)-2-phenylethanone and heated overnight under reflux. The reaction liquid was acidified by adding 1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography using ethyl acetate:n-hexane (1:9) as the elution solvent, thereby obtaining 227 mg of 2-[4-(1-naphthyl)-5-phenyl-1,3-thiazol-2-yl]pyridine as a colorless solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][C:7]=2[NH2:8])[CH2:3][CH2:2]1.CO[C:24](OC)(OC)[CH3:25]>CO>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:6]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:24]([CH3:25])=[N:8][C:7]=2[CH:9]=1
Reactant: COC(C)(OC)OC
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NCC1CC1
Solvent: CO
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 63.5 %

Procedure:
To a methanol (5 mL) solution of 2-(2-cyclopropylmethylaminoanilin-5-yl)benzoxazole (see Working Example 54-1) (140 mg, 0.425 mmol) was added 1,1,1-trimethoxyethane (75 mg, 0.624 mmol), and this was stirred at room temperature for 10 hours. After the reaction was complete, this was concentrated, and the residue obtained was purified by silica gel column chromatography to yield the title compound (81.9 mg, 54% yield) as pink crystals.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38]([CH:47]=O)=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH2:35][N:36]1[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:38](/[CH:47]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:37]1)[CH:29]=[CH:28]2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cn(Cc2ccc3cc(OCc4ccccc4)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Sodium hydride (60%, oily, 0.20 g) was added to a mixture of ethyl diethylphosphonoacetate (0.992 ml) and tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. A solution of 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2.09 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield ethyl(E)-3-[1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propenoate (1.65 g, yield: 68%). This was recrystallized from ethyl acetate-hexane. Melting point: 119–120° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]1([C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C(Cl)Cl>[CH3:25][O:24][C:22]([N:18]1[CH2:17][CH:16]=[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 105.2 %

Procedure:
Triethylamine (2.6 mL, 19.15 mmol) was added to a suspension of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.50 g, 7.66 mmol) in DCM (30 mL). The resulting mixture was stirred for 5 minutes until complete dissolution of the solids, then was cooled to 0° C., and methyl chloroformate (0.65 mL, 8.43 mmol) was added dropwise. A thick white precipitate formed. The reaction mixture was warmed to room temperature and stirred for 1 hour, then was quenched by addition of water, and extracted with DCM. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure to give 1.75 g of 4-phenyl-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester as a pale yellow oil. This crude product (7.66 mmol) was dissolved in chloroform (30 mL) and 3-chloroperoxybenzoic acid (77%, 2.22 g, 9.95 mmol) was added. The resulting solution was stirred at room temperature for 18 hours. An aqueous solution of Na2SO3 (20%, 30 mL) was added and the resulting mixture was vigorously stirred for 1 hour. The phases were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with a saturated aqueous solution of NaHCO3, dried over MgSO4, filtered and evaporated under reduced pressure to give a pale yellow oil. This crude oil was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 1.68 g (94% 2 steps yield) of 6-phenyl-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I.O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][CH2:23][CH2:24][O:25][CH3:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CCCO)nc3N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A solution of 160.0 mg (0.46 mmol) (4R,9aR)-6-(3-hydroxy-propyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 4 ml tetrahydrofuran was cooled to 0 deg C. and treated with 24.0 mg (0.51 mmol, 60% dispersion in mineral oil) sodium hydride. After 30 min 32 μl (0.51 mmol) methyl iodide was added and the cooling bath was removed. After 6 h another 0.64 μl (1.02 mmol) methyl iodide was added and the reaction was stirred overnight. The reaction mixture was poured into water and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant to afford the desired compound as a colorless oil (73.9%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.CN(C)C=O>O>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Temperature: 50 °C

Procedure:
A mixture of 2-chloro-3-nitropyridine (2C3NP, 138.1 Kg), 4-aminophenol (2.5-3 equivalents) and N,N-dimethylformamide (DMF, 4.8 mL/g 2C3NP) was stirred until homogeneous, heated at 50° C. during which an exotherm raised the solution temperature to 70° C., warmed to 80-85° C., stirred until no 2-chloro-3-nitropyridine remained, cooled to 30° C., treated with water (10.6 mL/g 2C3NP) to precipitate product, then with acetic acid (1.2 mL/g 2C3NP), then with ethyl acetate (0.5 mL/g 2C3NP), cooled to 5° C., stirred for 2 hours and filtered. The filtrant was washed sequentially with distilled water (1.6 mL/g 2C3NP), cold ethanol (1.2 mL/g 2C3NP) and cold isopropyl ether (1.2 mL/g 2C3NP), and dried under vacuum.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=3)[CH2:6][C:5]=12
Reactant: c1nnc2n1CCNC2
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCn5cnnc5C4)cc23)c1
Temperature: 80 °C
Reaction time: 36 h
Yield: 20.5 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.17 g) in DMF (8 mL) was added Ag2CO3 (1.29 g) and a solution of 6-(3-chloropropoxy)-N-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine (0.45 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (114 mg, 20.50%), HPLC: 90.63%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 456.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 3.99 (s, 1H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:7]=2[C:8]([NH:10][C:11]2([C:20](O)=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1.Cl.CN(C)CCCN=C=NCC.CO>CN(C)C1C=CN=CC=1.C(Cl)Cl>[NH:30]1[C:29]([NH:28][C:20]([C:11]2([NH:10][C:8](=[O:9])[C:7]3[CH:23]=[CH:24][CH:25]=[C:26]([CH3:27])[C:6]=3[O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:21])=[N:33][N:32]=[N:31]1
Reactant: Nc1nnn[nH]1
Reactant: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OC1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(=O)NC2(C(=O)Nc3nnn[nH]3)Cc3ccccc3C2)c1OC1CCC1
Yield: 68 %

Procedure:
A 40 mL tube is charged with 2-[(2-cyclobutoxy-3-methyl-benzoyl)-amino]-indan-2-carboxylic acid (323 mg, 0.884 mmol) and dry DCM (7 mL). A stirring bar is added and stirring is initiated. 5-Amino-1H-tetrazole (113 mg, 1.33 mmol) is added. To the resultant suspension, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (170 mg, 0.88 mmol) and 4-dimethylaminopyridine (108 mg, 0.88 mmol) is added. After 11½ days, tlc analysis (silica, 10% MeOH in DCM) indicates that the starting acid had been consumed. The reaction mixture is diluted with EtOAc (50 mL), transferred to an Erlenmeyer flask containing saturated aqueous ammonium chloride (50 mL). This mixture is allowed to stir. After 16 h of stirring, this mixture contained a white solid that is collected by suction filtration and washed with water (2×25 mL). Air drying gives 0.26 g of white powder.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: N[C@@H](CC(=O)O)c1ccccc1F
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1nc(C(=O)N[C@@H](CC(=O)O)c2ccccc2F)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 150 °C
Yield: 91 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-amino-3-(2-fluoro-phenyl)-propionic acid (86 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1800) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 91% yield. LC-MS ESI+: 472 (M+1)+; ESI−: 470 (M−1)−.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23].[OH-]>O1CCCC1.CO>[C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([C:13]3[S:14][C:15]([C:18]([O-:20])=[O:19])=[CH:16][N:17]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+:23]
Reactant: CCOC(=O)c1cnc(C2CCN(c3ccccc3)CC2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1cnc(C2CCN(c3ccccc3)CC2)s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(1-phenylpiperidin-4-yl)thiazole-5-carboxylate (31 mg, 0.098 mmol) in 1 ml of 1:1 tetrahydrofuran/methanol was treated with 1M aqueous LiOH (0.11 ml, 0.11 mol) and stirred at 65° C. for 3 hours. The mixture was taken to dryness and used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:14]=[CH:15][CH:16]=2)[C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[Br:17]N1C(=O)CCC1=O>ClCCl>[Br:17][C:16]1[CH:15]=[N:14][N:6]2[C:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[C:2]([CH3:1])[CH:3]=[N:4][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2ccnn2c1-c1cccnc1
Solvent: ClCCl
Product: Cc1cnc2c(Br)cnn2c1-c1cccnc1
Temperature: 0 °C

Procedure:
A mixture of 1.65 g. of 6-methyl-7-(3-pyridyl)pyrazolo[1,5-a]pyrimidine and 1.54 g. of N-bromosuccinimide in 50 ml. of dichloromethane is heated on a steam bath for 15 minutes. The mixture is poured into 100 ml. of ice cold 2.5 N sodium hydroxide. The dichloromethane layer is separated, dried over anhydrous sodium sulfate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 1.20 g. of the product of the example, m.p. 166°-168° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22]C1C=CC=CC=1B(O)O>>[CH3:21][O:22][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=1[C:14]=23
Reactant: COc1ccccc1B(O)O
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: COc1ccccc1-c1[nH]c2cccc3c2c1CCNC3=O

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 2-methoxyphenylboronic acid (189 mg, 1.24 mmol) were coupled to yield 2-(2-methoxy-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 177 mg (53%) as a brown solid: m.p. 254-255° C.; 1H NMR (300 MHz, d6-DMSO) DMSO) δ 2.81 (m, 2H), 3.36 (m, 2H), 3.83 (s, 3H), 7.08 (app t, J=7.5 Hz, 1H), 7.17 (m, 2H), 7.43 (m, 2H), 7.54 (dd, J=7.8, 0.6 Hz, 1H), 7.67 (dd, J=7.5, 0.6 Hz, 1H), 8.03 (br t, 1H), 11.27 (br s, 1H). MS (FAB, MH+) 293. Anal. (C18H16N2O2.0.3 H2O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:30]([CH:29]=[CH2:28])(=[O:32])=[O:31])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: O=S(=O)(Cl)CCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of N-(3-bromophenyl)-4,6-quinazolindiamine (315 mg, 1 mmol) and triethylamine (0.5 mL) in THF (50 mL) at 0° C. was dropwise added 2-chloroethylsulfonyl chloride (490 mg, 3 mmol). After the solution was stirred at 0° C. for 10 min, it was chromatographed on silica gel with 10% methanol in chloroform to give 212 mg of ethenesulfonic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide as an light yellow solid: HRMS (m/e): M+403.9937. Modified a method from A. A. Goldberg, J. Chem., Soc., 464 (1945).
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.O1CCCC1.C(OCC)(=O)C.Cl>O1CCCC1>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([CH:14]1[CH2:16][CH2:15]1)=[O:12]
Reactant: CON(C)C(=O)c1ccccc1C
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-methoxy-2,N-dimethylbenzamide (3.55 g) obtained in Step 1 in tetrahydrofuran (40 ml) was added dropwise a solution of 1M cyclopropylmagnesium bromide-tetrahydrofuran (29.7 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added a 4N hydrogen chloride-ethyl acetate solution (10 ml), and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (1.05 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.CO.[NH3:15].N.CO>C(Cl)Cl>[NH2:15][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(CBr)ccc1C#N
Reactant: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CN)ccc1C#N
Reaction time: 2 h

Procedure:
2.5 g of the bromide (b) were introduced into 10 ml of MeOH, and NH3 was passed in during dropwise addition of 38 ml of conc. ammonia/MeOH 1:1. After 2 h, the solvent was stripped off, the product was taken up in DCM and washed with water, and the organic phase was dried over Na2SO4. The product was precipitated as hydrochloride with ethereal HCl. 1H-NMR (DMSO-d6, δ in ppm): 8.6 (broad signal, NH3+), 7.79 (1H), 7.55 (1H), 7.20 (1H), 4.10 (s, 2H), 3.93 (s, 3H)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[H-].[Na+].[C:13]1([C@H:19]2[N:23]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:22][CH:21]([CH2:28]OS(C3C=CC(C)=CC=3)(=O)=O)[O:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH3:25][C:24]([N:23]1[CH2:22][CH:21]([CH2:28][O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[O:20][C@H:19]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:26])[CH3:27]
Reactant: OCCc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(C)(C)C)[C@H](c3ccccc3)O2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N1CC(COc2ccc(CCO)cc2)O[C@H]1c1ccccc1

Procedure:
4-(2-Hydroxyethyl)phenol (2.5 g, 18 mmol) was dissolved in 37 ml DMF then NaH (60% in mineral oil) (0.72 g, 18 mmol) was added while stirring under N2 atmosphere. After the evolution of H2 ceased, (S)-2-phenyl-5-tosyloxymethyl-3-(1,1-dimethylethyl) oxazolidine (7.0 g, 18 mmol) in 25 ml DMF was added and the reaction mixture was heated at 115°-120° C. for 14 hours. The solvent was evaporated in vacuo. A sodium carbonate solution (100 ml, 20% saturated) was added to the residue and the mixture was extracted with CHCl3 (150 ml then 100 ml). The chloroform was removed in vacuo and the residue was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:5]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: NCc1ccc(F)cc1F
Reactant: COC1CCC(OC)O1
Product: Fc1ccc(Cn2cccc2)c(F)c1

Procedure:
8.6 g (0.060 mol) of 2,4-difluorobenzylamine are heated in an autoclave with 8 g (0.060 mol) of 2,5-dimethoxytetrahydrofuran for 2 hours at 250° C. The reaction mixture is cooled and then purified by vacuum distillation. 9.2 g (79% of theory) of a colourless oil which boils at 110°-114° C. at 16 mbar are obtained.