Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[N:13]([CH2:25][C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:12]2=[O:32].C=O.[C:35]([BH3-])#N>C(#N)C.C(O)(=O)C.CO>[CH:29]([NH:28][C:26](=[O:27])[CH2:25][N:13]1[C:12](=[O:32])[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([N:2]3[CH2:3][CH:4]4[CH:5]([CH2:6][N:7]([CH3:35])[CH2:8]4)[CH2:1]3)[CH:10]=2)[N:15]=[C:14]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:30])[CH3:31]
Reactant: [BH3-]C#N
Reactant: CC(C)NC(=O)Cn1c(-c2ccccc2)nc2ccc(N3CC4CNCC4C3)cc2c1=O
Agent: C=O
Solvent: CO
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)NC(=O)Cn1c(-c2ccccc2)nc2ccc(N3CC4CN(C)CC4C3)cc2c1=O
Temperature: 130 °C
Yield: 39.1 %

Procedure:
2-(6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxo-2-phenylquinazolin-3(4H)-yl-N-isopropylacetamide (EXAMPLE 4A) (100 mg, 0.23 mmol) was dissolved in acetonitrile (2 mL) before addition of formaldehyde (28 mg, 0.35 mmol) and MP-cyanoborohydride (140 mg, 0.36 mmol) followed by 2 drops of acetic acid. The resulting solution was sealed in a microwave vial and heated at 130° C. for 20 minutes. Reaction mixture was then diluted with methanol before loading directly onto a 1 g SCX cartridge. The crude material was purified by SCX. The solvent was removed under reduced pressure and then re-dissolved in methanol (1 mL) and purified by preparative-HPLC. Purified sample was free-based using 500 mg SCX cartridge to afford N-isopropyl-2-(6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-oxo-2-phenylquinazolin-3(4H)-yl)acetamide (38 mg, 0.09 mmol).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:5].[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>N1C=CC=CC=1>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:2]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=2[C:4]([NH:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)=[O:5])[CH2:26][CH2:27]1
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: c1ccncc1
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-fluoro-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (150 mg) in anhydrous pyridine (3 mL) was added trans-4-aminocyclohexanol (81.4 mg), and the mixture was stirred for 15 hours at ambient temperature, and then for 3 hours at 60° C. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The eluent was concentrated and the residue was triturated with diisopropyl ether to give 2-(trans-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (164 mg).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[CH:15][C:14]=1[N+:32]([O-:34])=[O:33].CCCCCC>CS(C)=O>[N+:32]([C:14]1[CH:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH:20]=2)[CH:17]=[CH:18][C:13]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([O-:34])=[O:33]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(Nc1cccc(-c2ccc(F)c([N+](=O)[O-])c2)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COC(=O)C(C(=O)OC)c1ccc(-c2cccc(NC(=O)C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
Dimethyl malonate (9.6 mL) was added dropwise to a stirred suspension of 3.2 g of 60% sodium hydride in mineral oil in 40 mL of anhydrous dimethylsulfoxide under nitrogen. The mixture was stirred for 10 minutes and 2-fluoro-5-(3-trifluoroacetamidophenyl)nitrobenzene in 20 mL of dimethylsulfoxide was added. The resulting dark red mixture was heated to 100° C. for 2 hours. The reaction was quenched by pouring into 100 mL of saturated ammonium chloride solution and extracted twice with 50 mL of ethyl acetate each time. The organic phase was washed with 50 mL each of saturated ammonium chloride solution, water, and brine, dried over anhydrous sodium sulfate and concentrated to a yellow oil. The oil was chromatographed on a column of silica gel eluting with a 1:4 mixture of ethyl acetate:hexane to give 4.4 g (50% yield) of dimethyl 2-[2-nitro-4-(3-trifluoroacetamidophenyl)phenyl]malonate as a pale yellow solid.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([CH:53]=[CH:54][CH:55]=1)[NH2:52])=[N:31]2>>[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[N:33][C:32]([C:49]1[CH:50]=[C:51]([NH:52][C:1](=[O:4])[CH3:2])[CH:53]=[CH:54][CH:55]=1)=[N:31]2
Reactant: COc1cc(Oc2nc(-c3cccc(N)c3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1cc(Oc2nc(-c3cccc(NC(C)=O)c3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14.25 mg (0.24 mmol) of acetic acid, 32.06 mg (0.24 mmol) of HOBt, 72.00 mg (0.71 mmol) of 4-methylmorpholine, 50.03 mg (0.26 mmol) of EDC and 100 mg (0.24 mmol) of 3-[5,7-dimethyl-4-(3,4,5-trimethoxyphenoxy)imidazo[5,1-f][1,2,4]-triazin-2-yl]aniline from example 6 are reacted analogously to example 2.
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:9]([O:19][CH3:20])[CH:8]=1.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.O.Cl>O1CCCC1.CCCCCC>[CH:16]([O:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7]([B:21]([OH:26])[OH:22])=[CH:8][C:9]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1cc(I)cc(OC)c1OC(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(B(O)O)cc(OC)c1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
Under nitrogen, 10 mL (159 mmol) of a 1.59 mol/L hexane solution of n-butyl lithium and a solution of 23.0 g (71.4 mmol) of 1-iodo-4-isopropoxy-3,5-dimethoxybenzene in anhydrous tetrahydrofuran (100 ml) were added dropwise to anhydrous tetrahydrofuran cooled in a dry ice-methanol bath, and the mixture was stirred for 30 minutes. After addition of 20 mL (87 mmol) of triisopropyl borate, the reaction mixture was stirred for 15 minutes and the dry ice-methanol bath was removed. With stirring, the reaction mixture was allowed to warm to room temperature over about 1.5 hours. After addition of water (4 mL, 200 mmol), the mixture was concentrated under reduced pressure and the residue was dissolved in a 1 mol/L aqueous sodium hydroxide solution (200 mL). After washing with heptane (20 mL) and chloroform (3×15 mL), the resulting solution was stirred in an ice bath, followed by dropwise addition of 35 mL (420 mmol) of concentrated hydrochloric acid. The mixture was stirred with ice cooling for 2.5 hours. The precipitates were collected by filtration, washed with 0.1 mol/L hydrochloric acid and water and air-dried overnight, whereby 16 g of crude crystals were obtained. A solution of crude crystals in tetrahydrofuran (50 mL) was dried over magnesium sulfate and then concentrated under reduced pressure to about 25 mL. The residue heated to about 80° C. was stirred, and heptane (15 mL) was added. After stirring at room temperature and then, in an ice bath, precipitates were collected by filtration and washed with tetrahydrofuran-heptane (1:10:3×7.5 mL), whereby 12.75 g of 4-isopropoxy-3,5-dimethoxyphenylboronic acid was obtained as a colorless crystalline powder (mp: 211.5° C. (decomposed), yield: 71%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:11].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].Cl>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:15](=[O:16])[CH2:14][CH2:13][Cl:12])=[CH:10][C:5]=2[O:4][C:3]1=[O:11]
Reactant: O=C(Cl)CCCl
Reactant: Cn1c(=O)oc2ccccc21
Agent: Cl
Product: Cn1c(=O)oc2cc(C(=O)CCCl)ccc21
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
The flask is equipped with a reflux condenser and taken to an oil bath at a temperature in the region of 40°-45° C. 0.04 mole of 3-methylbenzoxazolinone and 0.44 mole of 3-chloropropionic acid chloride are introduced. The mixture is heated to a temperature in the region of 75° C. for 2 hours 30 minutes. After cooling, the reaction mixture is poured into 300 g of ice, acidified with concentrated hydrochloric acid and stirred for hour 30 minutes. The precipitate obtained is drained, washed with water and dried. The product is recrystallized in ethanol.
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([Cl:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:18][C:17]1[C:3]2[C:2]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]3)=[N:7][C:6]([NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)=[N:5][C:4]=2[NH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cn1cc(Nc2nc(Cl)c3c(Cl)c[nH]c3n2)cn1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1cc(Nc2nc(N3CCCC(NC(=O)OC(C)(C)C)C3)c3c(Cl)c[nH]c3n2)cn1
Yield: 44 %

Procedure:
A solution of 4,5-dichloro-N-(1-methyl-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (85 mg, 0.30 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (90 mg, 0.45 mmol) and DIEA (75 μL, 0.45 mmol) in DMSO (0.60 mL) was heated to 120° C. in a microwave for 10 min. The reaction solution was poured into water and filtered. The filtrate was extracted with EtOAc and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The solids were combined and purified via flash chromatography eluting with a gradient of 1%-5% of (10% NH4OH in MeOH) in DCM to give the title compound (59 mg, 44% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (br. s., 1H), 8.74 (s, 1H), 7.82 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=2.69 Hz, 1H), 6.89 (d, J=7.83 Hz, 1H), 3.96-4.11 (m, 2H), 3.78 (s, 3H), 3.51 (br. s., 1H), 2.85 (t, J=11.25 Hz, 1H), 2.75 (t, J=11.13 Hz, 1H), 1.85-1.94 (m, 1H), 1.75-1.84 (m, 1H), 1.70 (t, J=12.10 Hz, 1H), 1.38 (s, 9H), 1.31 (br. s., 1H). m/z (APCI+) for C20H27ClN8O2 447.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].OO.[OH2:32].C(O)(=[O:35])C>CCOCC>[Cl:1][CH2:2][CH2:3][S:4]([CH:5]([CH2:17][CH2:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:35])=[O:32]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCCl)OC(C)=O
Reactant: O
Reactant: CC(=O)O
Agent: OO
Solvent: CCOCC
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)S(=O)(=O)CCCl)OC(C)=O
Reaction time: 20 h

Procedure:
A solution of ethyl 8-(2-chloroethylthio)-12-acetoxyheptadecanoate (45.1 g., 0.1 mole) and 30% aqueous hydrogen peroxide (50 ml.) in acetic acid (225 ml.) is allowed to stand 20 hours at 25° C. The solution is diluted with 600 ml. of water. The oily product is taken up in ether, washed with dilute sodium bicarbonate solution and four portions of water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a light yellow viscous oil.
Reaction SMILES: [O:1]=[C:2]1[C@H:8]([NH:9][C:10](=[O:16])OC(C)(C)C)[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18].C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:10]([NH:9][C@H:8]3[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:2]3=[O:1])=[O:16])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: CCCNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCNC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-hexahydro-2-oxo-1-[(propylamino)carbonyl]-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white solid. LC-MS: 502 (M++1). 1H NMR (CD3OD) δ 0.95 (t, 3H), 1.55 (m, 4H), 1.90 (m, 3H), 2.10 (d, 1H), 3.10 (m, 4H), 3.25 (m, 3H), 3.65 (m, 4H), 4.80–4.95 (m, 4H), 5.86 (d, 1H), 6.12 (s, 1H), 7.12 (d, 1H), 7.58 (s, 1H), 7.65 (d, 1H), 9.00 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]([CH2:19][C:20]#[CH:21])([CH2:16][C:17]#[CH:18])[C:13](O)=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:23][OH:24]>>[OH:24][NH:23][C:13](=[O:14])[C:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])([CH2:19][C:20]#[CH:21])[CH2:16][C:17]#[CH:18]
Reactant: NO
Reactant: C#CCC(CC#C)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Product: C#CCC(CC#C)(C(=O)NO)S(=O)(=O)c1ccc(OC)cc1
Yield: 85 %

Procedure:
2-(4-Methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent4ynoic acid hydroxyamide was prepared according to the method as outlined in Example 1. Starting from (4methoxy-benzenesulfonyl)-2-prop-2-ynyl-pent-4-ynoic acid (0.25 g, 0.81 minol) and hydroxylamine hydrochloride (0.70 g, 10 mmol), 0.22 g of the product was isolated. Yield 85%; white solid; mp 156° C.; MS: 321.9 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.00-2.13 (m, 2H), 3.00-3.30 (m, 4H), 3.90(s, 3H), 7.01 (d, J=9.0 Hz, 2H), 7.82 (d, J =9.0 Hz, 2H), 8.76 (brs, 1H), 10.65 (brs, 1H); IR (KBr, cm-1): 3392s, 3293s, 3271m, 2955m, 1650s, 1594s; Anal. Calc'd for C15H15NO5S: C, 56.07; H, 4.70; N, 4.36.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.BrCC1OC(C(F)(F)F)=CC=1.[F:21][C:22]1[C:23]([F:40])=[CH:24][C:25]2[O:39][CH2:38][C:28]3([C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[C:26]=2[CH:27]=1.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28]3([C:26]4[CH:27]=[C:22]([F:21])[C:23]([F:40])=[CH:24][C:25]=4[O:39][CH2:38]3)[C:29]2=[O:37])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C12COc1cc(F)c(F)cc12
Reactant: BrCc1ccc(Br)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc(F)c(F)cc12

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 4-bromobenzyl bromide to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 1′-(4-bromobenzyl)-5,6-difluorospiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ7.51 (s, 1H), 7.48 (s, 1H), 7.23-7.04 (m, 5H), 6.82-6.77 (m, 2H), 6.50 (dd, J=8.9, 8.9 Hz, 1H), 5.03-4.96 (m, 2H), 4.84-4.72 (m, 2H); MS (ES+) m/z 442.1 (M+1), 444.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[O:1]=[C:2]1[NH:21][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([N:31]4[CH2:32][CH2:33][N:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[O:20])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Solvent: CN(C)C=O
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(c2ccccc2)CC1

Procedure:
This compound, m.p. 277°-279° C., obtained as a dimethylformamide solvate was prepared analogous to Example 15 from 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid and 4-phenylpiperazine.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2[CH:34]=[CH:33][C:32](CC(C)C)=[CH:31][CH:30]=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)C(C)C.C(OC(=O)C(C)(C1C=CC=CC=1)CCCCC(=O)CCCCC(C)(C1C=CC=CC=1)C(OCC)=O)C.[OH-].[K+]>C(O)C.O>[CH3:28][C:24]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:39])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:40])([C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13])[C:25]([OH:27])=[O:26]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: CCOC(=O)C(C)(CCCCC(=O)CCCCC(C)(C(=O)OCC)c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCCC(=O)CCCCC(C)(C(=O)O)c1ccccc1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
According to the procedure given for 210f, 209d (3.93 g, 7.9 mmol) was hydrolyzed with KOH (85%, 4.0 g, 60.6 mmol) in ethanol (60 mL) and water (10 mL) at reflux for 3 h and at room temperature overnight. After the usual workup and drying, 210d (3.0 g, 87%) was obtained as an oil. 1H NMR (CDCl3): δ 7.40-7.10 (m, 10 H), 2.32 (t, 4H, J=7.2), 2.10-1.80 (m, 4 H), 1.60-1.45 (m, 4 μl), 1.54 (s, 6 H), 1.25-1.10 (m, 4 H). 13C NMR (CDCl3): δ 211.1, 182.5, 142.8, 128.4, 126.9, 126.0, 49.9, 42.3, 38.7, 24.2, 24.0, 22.3. HRMS (LSIMS, nba): Calcd for C27H35O5 (MH+): 439.2484, found: 439.2497. HPLC: 93.7% pure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH2:12])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(O)c(N)c1
Yield: 98.4 %

Procedure:
Methyl(4-hydroxy-3-nitrophenyl)acetate [from step 3] (48.9 g, 0.23 mole) and 5% palladium on carbon were suspended in methanol and the resulting mixture was hydrogenated until all the starting material had been consumed. The reaction mixture was filtered to remove the catalyst and the filtercake was washed with methanol. The combined filtrate and washings were concentrated in vacuo, affording methyl(3-amino-4-hydroxyphenyl)acetate as a solid (41.0 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7](I)([CH3:9])[CH3:8].CN(C)C=O.[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1/[CH:32]=[CH:33]/[C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[OH:16][C@@H:17]1[CH2:31][C@@H:20]2[S:21][C@@H:22]([CH2:25][CH2:26][CH2:27][C:28]([O:30][CH:7]([CH3:9])[CH3:8])=[O:29])[CH2:23][CH2:24][C@@H:19]2[C@H:18]1[CH2:32][CH2:33][C@@H:34]([OH:43])[CH2:35][O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)I
Reactant: O=C(O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC[C@H]1CC[C@@H]2[C@@H](CC[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Under the argon atmosphere, cesium carbonate (68 mg) and isopropyl iodide (0.016 mL) were added to a dimethylformamide (0.4 mL) solution of the compound 15 (20) (42.8 mg), and the mixture was stirred at 50° C. for 90 minutes. This was cooled to room temperature, ethyl acetate was then added, and the mixture was washed with water two times, and then with a saturated saline once. The mixture was dried with anhydrous magnesium sulfate, and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3→1:1) to obtain a titled compound (34 mg) having the following physical property values.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[K].CC(C)([O-])C.Cl.[NH:21]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1>CS(C)=O>[N:21]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:25][CH2:24][C:23](=[O:26])[NH:22]1
Reactant: O=C1CCNN1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(=O)N2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
1.00 g (5.29 mmol) 4-fluoro-3-trifluoromethyl-benzonitrile are stirred together with 1.35 g (12.0 mmol) potassium-tert.-butoxide in 4 ml DMSO at ambient temperature under an argon atmosphere for 35 min and then 1.00 g (8.16 mmol) pyrazolidin-3-on-hydrochloride in 3 ml DMSO are added. After stirring at ambient temperature for 68 h the reaction mixture is poured into semisat. sodium chloride solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated down completely i. vac.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[ClH:24].[CH3:1][CH:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1
Reactant: CC1OCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1OCc2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-(5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.28 g, 0.87 mmol) in DCM (15 mL) was added 4N HCl in dioxane (5 mL). The mixture was stirred at room temperature overnight and then concentrated to give 5-methyl-4-(piperazin-1-yl)-5,7-dihydrofuro[3,4-d]pyrimidine dihydrochloride salt as an off white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.62 (bs, 2H), 8.72 (s, 1H), 5.72-5.71 (m, 1H), 5.55-5.00 (bs, 1H), 4.99-4.89 (m, 2H), 4.05-4.00 (m, 2H), 3.81-3.75 (m, 2H), 3.19-3.18 (m, 4H), 1.32 (d, J=8.4 Hz, 3H). LCMS (APCI+) m/z 221 [M+H+].
Reaction SMILES: [S-2:1].[Na+:2].[Na+].S.[C:5](Cl)(=[O:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O>[C:5]([O-:15])(=[S:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Na+:2]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: [S-2]
Agent: S
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCC([O-])=S
Temperature: 25 °C

Procedure:
Into a 2-liter round-bottomed flask was added 82 grams of sodium sulfide and 164 grams of water and the mixture was stirred at room temperature until the solids were dissolved. An excess of hydrogen sulfide was added below the surface until bubbling was seen in the trap. The reaction mixture was then cooled with an ice water bath to 17° C. Decanoyl chloride was then added slowly. Foaming was observed after about half of the decanoyl chloride had been added. At this point, the addition of decanoyl chloride was slowed and occasionally stopped to control foaming. The reactor temperature was kept at about 17° C. The decanoyl chloride addition was complete after a total of 2.5 hours. The pH of the resulting solution containing sodium thiodecanoate was measured with pH paper, giving an alkaline reading. An additional 2.7 grams of decanoyl chloride was then titrated into the solution to neutralize it, giving a final neutral pH reading.