Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[C:6]=2[CH2:5][CH2:4]1)=O.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH2:4][CH:3]2[CH2:1][N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)#[N:13]
Reactant: N#Cc1cccc2c1CCC2C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC2CCc3c(C#N)cccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Formyl-2,3-dihydro-1H-indene-4-carbonitrile (0.22 g, 1.3 mmol) was dissolved in MeOH (8 mL) and treated with tert-butyl piperazine-1-carboxylate (0.35 g, 1.9 mmol) followed by treatment of sodium cyanoborohydride (0.40 g, 6.43 mmol) and few drops of Acetic acid. The resulting mixture was then stirred at room temperature overnight. LC indicated completion of the reaction. The reaction mixture was concentrated in vacuo, treated with EtOAc and washed with saturated NaHCO3, dried with Na2SO4, filtered and loaded into MPLC for separation over silica gel. with 10% MeOH in DCM to afford tert-butyl 4-[(4-cyano-2,3-dihydro-1H-inden-1-yl)methyl]piperazine-1-carboxylate. This material was further treated with TFA to remove the Boc group. Removal of volatiles gave rise to 1-(piperazin-1-ylmethyl)indane-4-carbonitrile, which was used as the crude. LC-MS (IE, m/z): 242 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][OH:13])=[O:11].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[O:13][NH:12][C:10]1=[O:11]
Reactant: O=C(NO)Nc1ccc(Cl)cc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]oc(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of 4.2 g (19 mmol) of the compound of step A in tetrahydrofuran (20 mL) was treated with carbonyldiimidazole (3.2 g, 19 mmol). The mixture was stirred at 25° C. for 16 h. Some precipitated imidazole was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between 1N HCl (20 mL) and ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated to an oil which solidified to give 3.8 g of the title compound of Step B as a solid melting at 104-107° C. It was used directly for the next step without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:21][C:22]1[C:27]2[CH2:28][CH2:29][O:30][C:26]=2[C:25]([C:31]([NH:33][NH2:34])=O)=[CH:24][C:23]=1[Cl:35]>>[Cl:35][C:23]1[CH:24]=[C:25]([C:31]2[O:15][C:13]([CH:10]3[CH2:9][CH2:8][N:7]([CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH2:12][CH2:11]3)=[N:34][N:33]=2)[C:26]2[O:30][CH2:29][CH2:28][C:27]=2[C:22]=1[NH2:21]
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCC2
Reactant: O=C(O)C1CCN(C2CCOCC2)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(C3CCN(C4CCOCC4)CC3)o2)c2c1CCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 13.1 %

Procedure:
To 1-(tetrahydro pyran-4-yl) piperidine-4-carboxylic acid (168.2 mg, 0.58 mmol) was added phosphoryl chloride (1.76 mL). The mixture was stirred for 15 minutes and 4-amino-5-chloro-2,3-dihydro benzofuran-7-carboxylic acid hydrazide (101.2 mg, 0.0.44 mmol, obtained in preparation 3) was added. The reaction mixture was gradually heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The residual mass was purified by silica gel column to obtain 5-chloro-7-{5-[1-(tetrahydro pyran-4-yl) piperidin-4-yl]-[1,3,4]oxadiazol-2-yl}-2,3-dihydro benzofuran-4-yl amine (23.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([OH:20])=O)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][N:28](C=O)C.CN>C1COCC1.ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]([NH:28][CH3:27])=[O:20])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nc2ccc(Br)cn12
Reaction time: 0.08 h
Yield: 76 %

Procedure:
6-Bromo-2-(4-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxylic acid (250 mg, 0.746 mmol) was slurried into DCE (8 mL) and then oxalyl chloride (0.30 mL, 3.4 mmol) was added and the slurry was stirred for 5 min. Then DMF (50 μL, 0.65 mmol) was added (foaming) and the slurry was stirred 1 h before methanamine (5 mL, 10 mmol) 2M in THF (exothermic) and TEA (˜3 mL) (exothermic) were added. The reaction was stirred at rt overnight. The reaction was partitioned between water (˜30 mL) and DCM/MeOH (9/1, 3×30 mL). The combined organics were concentrated to dryness and the residue was slurried in MeOH/EtOAc (1:1 ˜40 mL) and filtered to collect 6-bromo-2-(4-fluorophenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide (172 mg, 0.494 mmol, 66% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.92 (s, 1H), 8.25 (s, 1H), 7.85 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 2.79 (d, J=4.0 Hz, 3H). LC-MS retention time 1.73 min; m/z 348, 350 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]([OH:22])=O)[CH:9]=[C:10]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC#N>[CH2:14]([O:13][C:10]1[CH:9]=[C:8]([CH:18]=[CH:19][C:20]([NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([C:32]([CH3:33])([CH3:35])[CH3:34])[C:29]([OH:36])=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:27]=2)=[O:22])[CH:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:11]=1[OH:12])[CH2:15][CH2:16][CH3:17]
Reactant: CC(C)(C)c1cc(CCN)cc(C(C)(C)C)c1O
Reactant: CCCCOc1cc(C=CC(=O)O)cc(OCCCC)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCCCOc1cc(C=CC(=O)NCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(OCCCC)c1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.5 %

Procedure:
To the solution of 3-(3,5-dibutoxy-4-hydroxyphenyl)acrylic acid (130 mg, 0.421 mmol), 4-(2-aminoethyl)-2,6-di-t-butylphenol (110 mg, 0.441 mmol) and HOBT (70 mg, 0.51 mmol) in MeCN 10 ml were DCC at 0° C. After 5 minutes, the solution was stirred for 2 hours at room temperature. And then the precipitate was removed by filtering it through a celite layer and the solution was poured into CH2Cl2. The solution was washed with 2N HCl and saturated NaHCO3 solution and the water was dried over anhydrous magnesium sulfate and filtered. The obtained filtrate was vacuum concentrated to give the residue, which was purified by column chromatography (EtOAc:Hexane=1:3), yielding 208 mg (91%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][C:29]=2[CH:39]=1)(=[O:24])=[O:23])[CH3:21]>>[CH2:20]([S:22]([C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([N:33]3[CH2:34][CH2:35][N:36]([C:8]([C:7]4[CH:11]=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:13]=[CH:14][C:6]=4[O:5][CH2:1][CH:2]([CH3:3])[CH3:4])=[O:10])[CH2:37][CH2:38]3)=[N:30][C:29]=2[CH:39]=1)(=[O:23])=[O:24])[CH3:21]
Reactant: CCS(=O)(=O)c1ccc2oc(N3CCNCC3)nc2c1
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCS(=O)(=O)c1ccc2oc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OCC(C)C)CC3)nc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isobutoxy-5-methanesulfonyl-benzoic acid (Example 2.4) and 5-ethanesulfonyl-2-piperazin-1-yl-benzoxazole hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate) to yield the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.ClC1C=CC=C(C(OO)=[O:20])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][CH:8]=[N+:9]([O-:20])[C:10]=2[CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cnc2cccnc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a stirred solution of 3-bromo-1,5-naphthyridine (C-2) (35.6 g, 170 mmol, 1.0 eq) in dichloromethane (300 mL) at 0° C. was added m-chloroperbenzoic acid (35.27 g, 204 mmol, 1.2 eq) in portions. The resulting mixture was stirred for 1 h at RT. The reaction was complete based on TLC analysis. The reaction mixture was washed with saturated Na2SO3 solution and saturated NaHCO3 solution sequentially, and then washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-5% MeOH-DCM) to afford the desired product 3-bromo-1,5-naphthyridine-5-oxide (C-3) (28.35 g, 74% yield). 1H NMR (300 MHz, CDCl3-d6) δ: 9.21 (s, 1H), 9.01 (s, 1H), 8.52 (d, J=6.3 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.53 (m, 1H); ESI-MS m/z: 208.10 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:26]1([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2F)[CH:32]=[O:33])[CH2:28][CH2:27]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:36]3[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][C:29]=3[CH:26]3[CH2:27][CH2:28]3)=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C2CC2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
N-(4-Chlorophenethyl)-4-hydroxybenzamide (504 mg, 1.83 mmol) was diluted with DMSO (8 mL) and K2CO3 (379 mg, 2.74 mmol) and 3-cyclopropyl-4-fluorobenzaldehyde (300 mg, 1.83 mmol) were added. The reaction was stirred 85° C. overnight. The reaction was cooled to ambient temperature, diluted with ethyl acetate and washed with twice with 10% sodium carbonate, water and brine, and concentrated. The crude material was purified by silica gel chromatography eluting with hexanes:ethyl acetate (3:1) to provide N-(4-chlorophenethyl)-4-(2-cyclopropyl-4-formylphenoxy)benzamide (160 mg, 20.9% yield).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][CH:1]=[O:3])=[CH:30][CH:31]=1
Reactant: O=CO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC=O)cc3)c2cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (0.13 ml) was added to acetic anhydride (0.27 ml), and the admixture was stirred at 60° C. for 2 hours. A solution of 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (303 mg) in tetrahydrofuran (8 ml) was added to the reaction mixture, and the admixture was stirred at room temperature for 45 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 327 mg of 6,7-dimethoxy-4-(4-formylaminophenoxy)quinoline.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[C:25]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C1C=CC=CN=1)C>CS(C)=O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:23][C:24]3[C:25]([N:30]4[C:31](=[O:40])[C:32]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:38]4=[O:39])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: O=C1c2ccccc2C(=O)N1c1ncccc1CBr
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N3C(=O)c4ccccc4C3=O)c3ccc(C#N)cc23)C1

Procedure:
Dissolve (S)-(7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl)-carbamic acid isopropyl ester (20 g, 70.59 mmoles; ee>98%, 2nd isomer on Chiracel OJ, 0.2% DMEA in Hexane/EtOH [80:20]) in dimethyl sulfoxide (160 mL) and add 2-(3-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (29.8 g, 84.71 mmol). Stir the mixture until a clear solution is obtained. Add cesium carbonate (46.4 g, 141.18 mmoles) and dimethylaminopyridine (875.5 mg, 7.06 mmol) in one portion. Stir the resulting mixture at 22/24° C. for 2 h. Add the mixture onto water (1.4 L). Stir the resulting suspension for 30 min and filter. Wash the resulting cake with water (100 ml). Dissolve the isolated wet solid in dichloromethane (750 mL) and separate the organic layer. Wash the organic layer with brine and evaporate the organic solvent. Purify the resulting material by silica gel chromatography, eluting with hexanes/acetone/CH2Cl2 (3/1/1) to obtain 24 g (58%). MS (m/z): 520 (M+1).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]([F:39])([F:38])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:23]([C:32]#[C:33][Si](C)(C)C)[CH:22]=1>C1COCC1.CCOC(C)=O>[C:32]([C:23]1[CH:22]=[C:21]([C:20]([F:19])([F:39])[F:38])[CH:26]=[CH:25][C:24]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29])#[CH:33]
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1cc(C(F)(F)F)ccc1CC(=O)OC

Procedure:
TBAF (1.0 M in THF; 7.16 mL, 7.15 mmol) was added to a stirred solution of methyl 2-(4-(trifluoromethyl)-2-((trimethylsilyl)ethynyl)phenyl)acetate (A58) (1.50 g, 4.77 mmol) in THF (50 mL) at 0° C. After 5 minutes the resulting mixture was diluted with EtOAc (50 mL) then washed with 10% NaHCO3 (50 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A59 as a dark red liquid (956 mg, 83%); 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=1.2 Hz, 1H), 7.57 (dd, J=8.1, 1.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 3.90 (s, 2H), 3.72 (s, 3H), 3.36 (s, 1H). LCMS-A: rt 6.099 min; m/z 243.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]1=[O:12].[OH:13]O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]1=[O:12]
Reactant: Cn1c(=O)cnc2ccccc21
Reactant: OO
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccccc21
Reaction time: 72 h

Procedure:
1-Methyl-2(1H)-quinoxalinone (5.3 grams) was allowed to stand at room temperature for 72 hours in a mixture of 60 ml. of acetic acid and 35 ml. of 30 percent hydrogen peroxide. The product separated out as needles after 48 hours. After 72 hours, no starting material was detectable in thesupernatant liquid by TLC (ethyl acetate). The product was separated and washed sequentially with water and with ethanol, m.p. 287°-289° C. It was then recrystallized from water, 287°-290° C. (literature: 286°-287° C., G. W. H. Cheeseman, J. Chem. Soc. 1804 (1955); 285°-286° C., G. W.H. Cheeseman, J. Chem. Soc. 1246 (1961)). NMR also confirmed the identity of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH:4]=O.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>CS(C)=O>[CH3:14][O:15][C:16]([C:17]1[CH:22]=[CH:21][C:20]2[N:23]=[C:4]([C:3]3[C:6]([C:10]([F:13])([F:12])[F:11])=[CH:7][CH:8]=[CH:9][C:2]=3[Cl:1])[NH:24][C:19]=2[CH:18]=1)=[O:25]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1c(Cl)cccc1C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-chloro-6-trifluoromethylbenzaldehyde (270 mg, 1.3 mmol) and 3,4-diaminobenzoic acid methyl ester (216 mg, 1.3 mmol) in DMSO (10 mL) was added Yb(OTf)3 (161 mg, 0.26 mmol) and the solution was stirred at ambient temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid methyl ester as a red oil. This was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1.[CH3:18]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:18])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[N:17]=1
Reactant: CC(=O)N(C)C
Reactant: COCCN1CCC(=O)Nc2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCCN1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.102 g (0.0004 mole) of 2-chloro-9-(2-methoxy-ethyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-40), 1 mL of N,N-dimethylacetamide and 0.037 mL (0.0006 mole) of iodomethane at 0 degrees was added 0.024 g (0.0006 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.087 g of 2-chloro-9-(2-methoxy-ethyl)-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-40) as an yellow solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[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[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[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[CH2:34][CH2:33][N:32]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f38) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][C:12]=3[C:13]=2[CH3:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+]>O1CCCC1.CO>[CH:1]1([CH:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[CH:15][C:12]=3[C:13]=2[CH3:14])[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSCCCOc1ccc2oc(C(=O)C3CCCCC3)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCCOc1ccc2oc(C(O)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
Cyclohexyl{3-methyl-5-[3-(methylsulfanyl)propoxy]-1-benzofuran-2-yl}methanone (3.1 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (50 mL) and methanol (10 mL), and sodium borohydride (90%, 0.73 g) was added to the solution under ice-cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (5 mL) and 1N hydrochloric acid (25 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.0 g, 95%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH:39]1(Br)[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([N:34]2[CH2:35][CH2:36][C:31]3([C:28]4[C:27](=[CH:26][C:25]5[CH2:24][CH2:23][N:22]([C:20]([C:17]6[CH:18]=[CH:19][C:14]([C:3]7[CH:4]=[CH:5][C:6]([N:8]8[CH2:12][CH2:11][CH2:10][C:9]8=[O:13])=[CH:7][C:2]=7[CH3:1])=[CH:15][CH:16]=6)=[O:21])[C:30]=5[CH:29]=4)[O:38][CH2:37]3)[CH2:32][CH2:33]2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Reactant: BrC1CCCC1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C3CCCC3)CC2)CO4)cc1

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and cyclopentyl bromide using a similar procedure to Example 19, as a white powder (22%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[C:5]#[N:6]>CO.[Ni]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(F)cc(F)c1
Agent: [Ni]
Solvent: CO
Product: NCc1cc(F)cc(F)c1
Reaction time: 1.5 h

Procedure:
A mixture of 3,5-difluorobenzonitrile (13.9 g., 0.10 mole) in methanol [(140 ml.), saturated with ammonia]and Raney nickel was shaken under hydrogen (50 psi.) for 1.5 hours and the solution was decanted from the catalyst. The solution was filtered, evaporated to an oil, and dissolved in ethyl acetate. The ethyl acetate solution was extracted twice with 1N HCl (75 ml.) and the aqueous solution was washed once with ethyl acetate, made basic with 10% sodium hydroxide, and extracted with three portions of ethyl acetate (100 ml.). The ethyl acetate solution was washed with water and brine, dried, and the solvent removed under vacuum. The residue was diluted with ether, filtered, and the solvent was removed under vacuum to give 3,5-difluorobenzylamine as an oil (11.7 g., 82%).