Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]2[O:9][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:12]>CC(C)=O>[OH:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH:2]=[CH2:1])[CH2:8][CH:7]1[OH:12]
Reactant: O=S(=O)(O)O
Reactant: C=CC1CCC2OC2C1
Solvent: CC(C)=O
Solvent: O
Product: C=CC1CCC(O)C(O)C1

Procedure:
Into a two-neck flask (100 ml) were fed 15.9 g (128 mmol) of 4-vinylcyclohexene-1,2-epoxide, 40 ml of water, 20 ml of acetone, and 40 μl of sulfuric acid, and the reaction mixture was refluxed at 75° C. for 4 hours. After complete reaction, an object compound was extracted with each 60 ml of diethylether four times, and was washed with saturated salt solution, and then was dried with sodium sulfate. The solvent was evaporated to obtain 1,2-dihydroxy-4-vinylcyclohexane.
Reaction SMILES: C(O[C:4]1([O:10]CC)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)C.C(Cl)(Cl)Cl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(N(CC)CC)C>[C:18]([N:6]1[CH2:7][CH2:8][CH2:9][C:4](=[O:10])[CH2:5]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)Cl
Reactant: CCOC1(OCC)CCCNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCCC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 8.7 g. of 3,3-diethoxypiperidine in 100 ml. of dry chloroform is treated at 0° C. with 5 g. of triethylamine followed by 5.4 g. of ethyl chloroformate. After stirring at 25° C. for two hours, the solvent is removed in vacuo. The residue is extracted with ether and the extract concentrated in vacuo. This residue is treated with dilute hydrochloric acid for two hours. The solution is then saturated with sodium chloride and extracted with chloroform. The chloroform extract is washed with 5% aqueous sodium bicarbonate solution, dried and concentrated in vacuo to give 1-carbethoxy-3-piperidone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccc(F)cc2)Oc2ccc(Br)cc21
Yield: 22.2 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (30 g, 0.14 mol), 4-fluorobenzaldehyde (19.3 g, 0.14 mol) and borax (53.34 g, 0.14 mol) in ethanol (180 mL) and H2O (300 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(4-fluoro-phenyl)-chroman-4-one (10 g, 20%). 1H-NMR (CDCl3): 2.81 (dd, 1H), 2.99 (t, 1H), 5.49 (dd, 1H), 6.87 (d, 1H), 7.04 (t, 2H), 7.38 (t, 2H), 7.51 (dd, 1H), 7.94 (d, 1H).
Reaction SMILES: [CH:1]1([CH2:9][OH:10])[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.CC(C)([O-])C.[K+].[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29](F)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1.Cl>CS(C)=O>[N:17]1([S:21]([NH:24][C:25](=[O:35])[C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:10][CH2:9][CH:1]3[C:3]4([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH2:2]3)=[CH:28][C:27]=2[F:34])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F
Reactant: OCC1CC12CCCCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC2CC23CCCCC3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of spiro[2.5]octan-1-ylmethanol (prepared according to Huang and Forsyth, Tetrahedron 1997, 53, 16341) (0.40 g, 2.87 mmol) in anhydrous dimethylsulfoxide (5 mL) was added potassium tert-butoxide (0.81 g, 7.24 mmol) and the reaction mixture was stirred for 30 minutes at ambient temperature. To this reaction mixture was added N-(azetidin-1-ylsulfonyl)-5-chloro-2,4-difluorobenzamide (0.90 g, 2.89 mmol) and stirred for 2 hours. The mixture was poured into 1 M aqueous hydrochloric acid, the layers were separated and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine; dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 30% ethyl acetate in hexanes) to afford the title compound (0.49 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.81 (br s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.26 (d, J=12.5 Hz, 1H), 4.35-4.31 (dd, J=10.9, 6.3 Hz, 1H), 4.04 (t, J=7.7 Hz, 5H), 2.17 (q, J=7.7 Hz, 2H), 1.77-0.94 (m, 11H), 0.57-0.55 (dd, J=8.5, 4.3 Hz, 1H), 0.30 (t, J=4.7 Hz, 1H); MS (ES−) m/z 429.20 (M−1).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH:4]1[C:9](=O)[CH2:8][CH2:7][O:6][CH2:5]1.Cl.[NH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:11][C:2]1[N:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]2[CH2:8][CH2:7][O:6][CH2:5][C:4]=2[CH:3]=1
Reactant: CC(=O)CC1COCCC1=O
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)cc2c1CCOC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
3-(2-oxopropyl)dihydro-2H-pyran-4(3H)-one (0.41 g, 2.63 mmol) in dichloromethane (3 ml) was stirred at room temperature, and ethyl 2-aminoacetate hydrochloride (0.366 g, 2.63 mmol) was added, followed by sodium bicarbonate (0.441 g, 5.25 mmol). The resulting mixture was stirred at 25° C. for 15 hours, after which TLC showed that the reaction was complete. DCM was added, the organic layer was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed on silica gel using an automated Biotage system, EtOAc/Hexane 5-30%, to give the desired product (0.41 g, yield 70%). 1H NMR (400 MHz, CDCl3) δ (ppm) 5.69 (s, 1H), 4.62 (s, 2H), 4.44 (s, 2H), 4.21 (q, 2H), 3.95-3.94 (m, 2H), 2.58-2.55 (m, 2H), 2.18 (s, 3H), 1.28 (t, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:23]=[CH:24]/[C:25]([OH:27])=O)[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1.[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40]CC2C=CC=CC=2)[C:35]=1[C:48](=[O:50])[CH3:49]>>[C:48]([C:35]1[C:36]([OH:40])=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:28][C:25](=[O:27])[CH2:24][CH2:23][C:11]1[CH:12]=[CH:13][C:14]([N:15]2[CH2:19][C:18](=[O:20])[NH:17][S:16]2(=[O:21])=[O:22])=[C:9]([OH:8])[CH:10]=1)(=[O:50])[CH3:49]
Reactant: CC(=O)c1c(OCCCCN)cccc1OCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Product: CC(=O)c1c(O)cccc1OCCCCNC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
The title compound is prepared using (E)-3-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-acrylic acid and 1-[2-(4-aminobutoxy)-6-benzyloxyphenyl]-ethanone analogous to Example 100 steps C and D: (M−1)−=504. HPLC retention time: 1.09 min. (Method A).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH2:34]([N:36]1[CH2:41][CH2:40][N:39]([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1)[CH3:35]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:16][CH2:17]1)=[O:29])[C:7]([N:45]1[CH2:44][CH2:43][CH:42]([N:39]2[CH2:38][CH2:37][N:36]([CH2:34][CH3:35])[CH2:41][CH2:40]2)[CH2:47][CH2:46]1)=[O:8]
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Reactant: CCN1CCN(C2CCNCC2)CC1
Product: CCN1CCN(C2CCN(C(=O)C(CC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)Cc3ccc(C)c(C)c3)CC2)CC1

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-ethyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C1COCC1>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[S:15][C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[N:13][C:12]=2[C:27]([NH2:29])=[O:28])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: O=C(Cl)CC1CCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A solution of 2-cyclopentylacetyl chloride (0.35 mL, 2.64 mmol) in THF (2 mL) was added dropwise to a mixture of 5-amino-2-(naphthalen-2-ylamino) thiazole-4-carboxamide (0.15 g, 0.53 mmol) and pyridine (2 mL) in THF (10 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed successively with ether and EtOAc to give 0.12 g (58% yield) of the titled compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([CH:3]([NH2:2])[C:4]#[N:5])=[O:10]
Reactant: N#CCN
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#CC(N)C(=O)c1ccccc1F
Reaction time: 8 h

Procedure:
14.8 g Aminoacetonitrile hydrochloride was dissolved in 80 ml water. The solution was stirred while 25.37 g 2-fluorobenzoylchloride and a solution of 21.2 g sodium carbonate in 120 ml water were dropped simultaneously from two dropping funnels into it. The mixture was stirred overnight. The precipitate was filtered by suction and recrystallised from methanol plus water, filtered and dried.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:15])[F:14])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([F:14])[F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@H:29]4[CH2:33][C@H:32]([CH3:34])[N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CN[C@@H](C)C1
Agent: Cl
Product: CCC(=O)N1C[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-N-[(3S*,5S*)-5-methylpyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f66) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH:2]([C:4]1[N:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1)[CH3:3].[Na].[CH3:15][SH:16].O>CN(C=O)C>[CH3:15][S:16][CH:2]([C:4]1[N:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[N:5]=1)[CH3:3]
Reactant: COc1cc(OC)nc(C(C)Cl)n1
Reactant: CS
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C)SC)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
2-(1-Chloroethyl)-4,6-dimethoxypyrimidine 15.5 g (76.5 mmol) was dissolved in DMF 200 ml and sodium salt of methylmercaptan 5.4 g (76.5 mmol) was added thereto at room temperature. The solution was stirred at 50° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The solvent was distilled off and the residue was purified with column chromatography (hexane/ethyl acetate=5/1) to obtain 2-(1-methylthioethyl)-4,6-dimethoxypyrimidine 14.8 g (90%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[Cl:19])[C:4]1=[O:20].C(N(CC)CC)C.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[C:29]1[S:37](Cl)(=[O:39])=[O:38]>CC#N>[Cl:19][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C@H:3]([NH:2][S:37]([C:29]4[S:28][C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[CH:30]=4)(=[O:38])=[O:39])[C:4]3=[O:20])[CH:10]=2)[N:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N[C@H]1CCN(Cc2ccc3nccc(Cl)c3c2)C1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccccc3s2)CCN1Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
3-(S)-Amino-1-(4-chloroquinolin-6-ylmethyl)-pyrrolidin-2-one hydrochloride (0.12 g, 0.38 mmol) is suspended in 15 mL CH3CN. To this solution is added triethylamine (110 mL, 0.79 mmol) followed by benzothiophene-2-sulfonyl chloride (0.094 g, 0.40 mmol). The mixture is stirred overnight at room temperature, subjected to aqueous work up then concentrated to dryness. The crude product is purified by column chromatography eluting with 2-10% MeOH/CH2Cl2 to give the title compound (0.11 g, 0.23 mmol) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH3:51][O:52][CH2:53][CH2:54]O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:54][CH2:53][O:52][CH3:51])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: COCCO
Product: COCCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 3c from 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 18 μL (0.23 mmol) 2-methoxy-ethanol.
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:17])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=2)=[O:4].[Na+].[NH2:19][CH2:20][C:21]([O-:23])=[O:22]>COCCO>[Br:16][C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:4])[C:6](=[O:17])[O:7]2)=[CH:12][CH:11]=1
Reactant: NCC(=O)[O-]
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Agent: [Na+]
Solvent: COCCO
Product: O=C(O)CNC(=O)c1c(O)c2ccc(Br)cc2oc1=O
Yield: 99.1 %

Procedure:
A mixture of 7-bromo-4-hydroxy-2-oxo-2H-chromene-3-carboxylic acid methyl ester (example 11-b) (2.835 g, 9.47 mmol) and glycine sodium salt (13.8 g, 142.12 mmol) in 2-methoxyethanol (100 mL) was refluxed for 6 h; then cooled, solvent was evaporated, the residue was dissolved in water and acidified with 2 M HCl solution; the precipitates were collected via filtration, washed with water and air dried to give the desired title product (3.209 g). 1H NMR (200 MHz, DMSO-d6): δ (ppm)=18-12 (br, 2H), 9.79 (br, 1H), 7.85 (d, 1H, J=8.4 Hz), 7.7-7.5 (m, 2H), 4.05 (d, 2H, J=5.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[OH:10].[CH3:11][C:12]1([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C([BH3-])#N.C(O)(=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH:9][CH:21]2[CH2:22][CH2:23][N:18]([C:12]3([CH3:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:19][CH2:20]2)[C:3]=1[OH:10]
Reactant: Cc1cc(N)c(O)c(F)c1
Reactant: CC1(N2CCC(=O)CC2)CCOCC1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(F)c(O)c(NC2CCN(C3(C)CCOCC3)CC2)c1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
2-Amino-6-fluoro-4-methylphenol (D16, 49 mg, 0.34 mmol) was dissolved in DCM (3 mL) and 1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinone (D12, 68 mg, 0.34 mmol), polymer supported cyanoborohydride (160 mg, 0.69 mmol, 4.3 mmol/g) and acetic acid (0.10 mL, 1.72 mmol) were all added at room temperature. The mixture was reacted at 100° C. in the microwave for 10 min. The mixture was then cooled to room temperature, filtered and the solvent was removed under vacuum to give the crude product, an orange oil, which was purified via flash column chromatography (silica, DCM to 0.5% NH3/9.5% MeOH/90% DCM) to give 2-fluoro-4-methyl-6-{[1-(4-methyltetrahydro-2H-pyran-4-yl)-4-piperidinyl]amino}phenol (D17, 51 mg, 42%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[NH:16][C:17](=[S:19])[S:18]/1.[CH3:21]CN(C(C)C)C(C)C.IC>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2/[CH:13]=[C:14]1/[C:15](=[O:20])[N:16]=[C:17]([S:19][CH3:21])[S:18]/1
Reactant: COc1ccc2[nH]c(C)c(/C=C3\SC(=S)NC3=O)c2c1
Reactant: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: CO
Product: COc1ccc2[nH]c(C)c(/C=C3\SC(SC)=NC3=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a room temperature suspension of (Z)-5-[(5-methoxy-2 methyl-1H-indol-3-yl)methylene]-2-thioxo-4-thiazolidinone (1.714 g, 5.63 mmols) in 50 mL of methanol is added Hunig's base (1.15 mL, 6.61 mmols) followed by iodomethane (0.500 mL, 8.03 nmmols). The thick suspension is stirred overnight at room temperature. Filtration washing with ether provides 1.631 g (91%) of (Z)-5-[(5-methoxy-2-methyl-1H-indol-3-yl)methylene]-2(methylthio)-4(5H) thiazolone; mp 214-222° C. dec. Calc'd for C15H14N2O2S2 :
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13]>>[C:11]1(=[O:15])[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]=[CH:3][CH2:2][N:1]3[C:12]1=[O:13]
Reactant: C1=Cc2ccccc2NC1
Reactant: O=C(Cl)C(=O)Cl
Product: O=C1C(=O)N2CC=Cc3cccc1c32

Procedure:
Generally speaking, the reaction of a 1,2-dihydroquinoline (II) with oxalyl chloride (III) to give a 4-H-pyrrolo[3,2,1-ij]quinolin-1,2-dione (I) is carried out in a dry aprotic solvent by the dropwise addition of a solution of the 1,2-dihydroquinoline in the same solvent to the stirred solution of oxalyl chloride in an inert atmosphere at or near room temperature. Subsequent to the addition the reaction mixture is briefly stirred at ambient temperature and then at gentle reflux to complete the reaction. The solvent is stripped from the reaction mixture at reduced pressure to give a solid residue which on crystallization from a selected solvent or solvent system furnishes the 4-pyrrolo[3,2,1-ij]quinoline-1,2-dione I.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH2:14])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1.[H-].[Na+].C(N(CC)C(C)C)(C)C.[OH:26][C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:32][CH2:31][N:30]([C:33](Cl)=[O:34])[CH2:29][CH2:28]1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:13]=[C:12]([NH:14][C:33]([N:30]3[CH2:29][CH2:28][C:27]([OH:26])([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:44])([F:43])[F:45])[CH:37]=4)[CH2:32][CH2:31]3)=[O:34])[S:11][C:5]=2[N:6]=[C:7]([S:9][CH3:10])[N:8]=1
Reactant: COc1nc(SC)nc2sc(N)nc12
Reactant: O=C(Cl)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(SC)nc2sc(NC(=O)N3CCC(O)(c4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
A magnetically stirred mixture of 7-Methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-ylamine (500 mg, 2.19 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere at 25° C. was treated with sodium hydride (60% suspension in mineral oil, 265 mg, 6.58 mmol). The reaction mixture was stirred at 50° C. for 1 h. At this time, the reaction was cooled to room temperature and was treated with N,N-diisopropylethylamine (850 mg, 6.58 mmol) and 4-hydroxy-4-[3-(trifluoromethyl)phenyl]piperidine-1-carbonyl chloride (810 mg, 2.63 mmol). The reaction mixture was stirred at room temperature for 3 d. At this time, the reaction was concentrated in vacuo, poured into water and extracted with ethyl acetate. The organics were washed with a 2N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98:2 methylene chloride/methanol) afforded 4-hydroxy-4-[3-(trifluoromethy)phenyl]piperidine-1-carboxylic acid (7-methoxy-5-methylsulfanyl-thiazolo[5,4-d]pyrimidin-2-yl)-amide (375 mg, 34%) as a red solid. LRMS for C20H20F3N5O3S2 (M+H)+ at m/z=499. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:56])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:48][CH3:49])[C@H:43]([C:45](O)=[O:46])[CH3:44])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:57][C@H:58]1[NH:62][C:61](=[O:63])[NH:60][C@H:59]1[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][C:69]([NH:71][CH2:72][CH2:73][NH:74][C:75](=[O:85])[C@H:76]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH2:77])=[O:70].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:52]([CH3:55])[CH2:53][CH3:54])[C@H:33]([O:50][CH3:51])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@@H:42]([C@@H:43]([CH3:44])[C:45](=[O:46])[NH:77][C@@H:76]([CH2:78][C:79]3[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=3)[C:75](=[O:85])[NH:74][CH2:73][CH2:72][NH:71][C:69](=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][C@H:59]3[C@@H:58]([CH3:57])[NH:62][C:61](=[O:63])[NH:60]3)[O:48][CH3:49])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:56])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H]1NC(=O)N[C@H]1CCCCCC(=O)NCCNC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCNC(=O)CCCCC[C@@H]1NC(=O)N[C@@H]1C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Yield: 27.4 %

Procedure:
Following general procedure D using #105 (36.6 mg, 0.047 mmol, 1.0 eq.), #255 (19 mg, 0.047 mmol, 1.0 eq.), HATU (22.4 mg, 0.056 mmol, 1.2 eq.) and Hunig's base (0.025 mL, 0.141 mmol) in 1.5 mL of DMF following by purification (Method J) yielded #256 (15 mg, 27%) as a white solid. LC-MS (Protocol Q1): m/z 1164.8 [M+H+], retention time=0.99 minutes.