Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[S:31]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride.
Reaction SMILES: [NH2:1][C:2](=[O:16])/[C:3](/[C:14]#[N:15])=[N:4]/[NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[Br:13].[Al+3].[Cl-].[Cl-].[Cl-].C1(C)C=CC=CC=1.Cl>CCO>[NH2:15][C:14]1[C:11]2[C:6](=[C:7]([Br:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[N:4][C:3]=1[C:2]([NH2:1])=[O:16]
Reactant: N#C/C(=N\Nc1cc(F)ccc1Br)C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: NC(=O)c1nnc2c(Br)ccc(F)c2c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
(E)-2-Amino-N′-(2-bromo-5-fluorophenyl)-2-oxoacetohydrazonoyl cyanide (10 g, 35 mmol), AlCl3 (20 g, 4.0 eq), and toluene (200 mL) were stirred at 120° C. overnight under N2. The reaction mixture was subsequently cooled to 0° C. and 2N HCl (200 mL) was added. The reaction mixture was stirred at 0° C. for 10 minutes and then filtered to afford a crude solid (4.5 g), which was dispersed in EtOH (500 mL). The mixture was stirred at RT for 4 hours and filtered. The filtrate was concentrated to give the title compound (1.5 g, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (1H, s), 8.62 (1H, s), 8.23-8.20 (1H, m), 8.00 (1H, s), 7.80 (1H, s), 7.47-7.42 (1H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 3.020 minutes) ESI+APCI m/z [M+H]+ 285.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.C(OCC)(=O)C>CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([C:13]#[CH:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (5-trimethylsilanylethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.67 g, 5.633 mmol) was dissolved in methanol (20 ml) was added K2CO3 (0.389 g, 2.816 mmol) and stirred at room temperature overnight. Then the reaction was heated at 50° C. for 2 hrs. Methanol was removed under reduced pressure. The residue obtained was partioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (5-ethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Br)C=C.C(OCC)C.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:34][C:33](=[O:35])[C:32]3[CH:36]=[N:37][CH:38]=[CH:39][C:31]=3[N:30]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([NH:30][C:31]2[CH:39]=[CH:38][N:37]=[CH:36][C:32]=2[C:33]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:35])=[O:34])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(-c2nc3ccncc3c(=O)o2)cc1
Reactant: Nc1ccc(Cl)cn1
Agent: C=CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccncc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a stirring solution of 2-amino-5-chloropyridine (0.11 g, 0.85 mmol) in THF (12 mL) at 0° C. was added a 1 M solution of allylmagnesium bromide in diethyl ether (0.83 mL, 0.83 mmol). After 20 min, 2-[4-t-butylphenyl]-4H-6-aza-3,1-benzoxazin-4-one (0.115 g, 0.41 mmol) was added and the cold bath was removed. After 2 h, the mixture was diluted with ethyl acetate and washed three times with brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The solid was recrystallized from diethyl ether then washed several times with mixtures of ether/hexanes and dried to give 0.138 g (82%) of pale yellow needles.
Reaction SMILES: N([Si:4]([CH3:7])([CH3:6])[CH3:5])=[N+]=[N-].[CH:8]12[O:13][CH:9]1[CH2:10][CH2:11][CH2:12]2.C([I:17])C=C>ClC1C=CC=CC=1>[I:17][C@H:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[O:13][Si:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: C1CC2OC2C1
Reactant: C=CCI
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Clc1ccccc1
Product: C[Si](C)(C)O[C@H]1CCC[C@@H]1I
Yield: 65 %

Procedure:
To a vial containing 0.03 grams of (S)-catalyst prepared as in Example 4 was added a solution of azidotrimethylsilane (0.17 g, 1.47 mmol), cyclopentene oxide (0.10 g, 1.19 mmol), and allyl iodide (0.41 g, 2.44 mmol) in chlorobenzene (3.0 mL). After 48 h the volatiles were removed at reduced pressure and the residue was purified by flash chromatography on 220-400 mesh silica with 98% hexane and 2% ether as eluant. The product (1S,2S)-1-iodo-2-trimethylsiloxycyclopentane (0.22 g, 75%) was isolated by distillation of the solvent. Anal. for C8H17OSiI. Calcd: C, 33.81; H, 6.03; 1, 44.65. Found: C, 34.60; H. 5.79; I, 44.21. 1 H NMR (CDCl3/TMS): δ 0.13 (s, 9 H), 1.53 (m, 1 H), 1.77 (m, 2 H), 1.97-2.12 (m, 2 H), 2.32 (m, 1 H), 4.01 (m, 1 H), 4.42 (m, 1 H). 13C NMR (CDCl3/TMS): δ 0.11, 22.37, 32.35, 34.64, 35.96, 82.48. [a]D25=+86.4°, c=1.04 g/100 mL chloroform. Chiral capillary gas chromatographic analysis at 110° C. on Cyclodex B stationary phase indicated that the enantiomeric excess of the product was 95%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:20]([OH:24])[CH:21]([CH3:23])[CH3:22])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C@@H:20]([OH:24])[CH:21]([CH3:22])[CH3:23])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](O)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 109.9 %

Procedure:
A solution of tert-butyl (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoate (400 mg, 1.19 mmol) in methylene chloride (7 ml) was cooled to 0° C. under nitrogen atmosphere. To this solution was added trifluoroacetic acid (10 ml), and the resulting mixture was warmed up to room temperature and stirred for 2.5 hours. The volatiles were removed in vacuo to provide (2S,3S)-2-{[(benzyloxy)carbonyl]amino}-3-hydroxy-4-methylpentanoic acid (368 mg, 100%) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]2[C:19]([OH:25])=[CH:20][CH:21]=[C:22]([F:24])[CH:23]=2)[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:10])=[O:9].CC1C=CC(S(O[C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25][C@@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:5]=[CH:6][C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)(=[O:10])=[O:9]
Reactant: COC(=O)[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc(-c2cc(F)ccc2O)cc1F
Product: COC(=O)[C@H](C)Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2cccc(F)c2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 11 step (vii) using the product of step (iv) and the product of example 11 step (vi).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:23]([OH:25])=[O:24])[CH:12]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH2:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:27]>C(Cl)Cl.CO>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][CH:11]([C:23]([O:25][CH3:27])=[O:24])[CH:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[CH2:18][C:19]([F:22])([F:21])[F:20])(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)s1)C(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Yield: 21.3 %

Procedure:
To a solution of N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvaline (1.3 g, 5.23 mmol) in CH2Cl2:MeOH (4:1) TMSCHN2 (6 mL, 12 mmol) was added dropwise over 10 min at 0° C. until a neon yellow color persisted. When the dropwise addition was completed, the reaction mixture was allowed to warm to 25° C. over 19 h. The solvent was removed in vacuo to obtain methyl N-[(5-chlorothien-2-yl)sulfonyl]-5,5,5-trifluoro-3-(2,2,2-trifluoroethyl)-dl-norvalinate (0.5 g, 37.31%). Mass Spectrum (−ESI): 445 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13](O)=O)=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:24][C:25]1[C:26](=[S:40])[NH:27][C:28]([C:31]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:33][CH2:32]2)=[CH:29][CH:30]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[CH:16][C:12]([C:13]2[S:40][C:26]3[C:25]([N:24]=2)=[CH:30][CH:29]=[C:28]([C:31]2([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH2:32][CH2:33]2)[N:27]=3)=[CH:11][C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2(c3ccccc3)CC2)[nH]c1=S
Reactant: Cc1cc(C(=O)O)cc(C)c1OCc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc(C)c1OCc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 4-(benzyloxy)-3,5-dimethylbenzoic acid (238.0 mg, 929 μmol) and thionyl chloride (2.5 mL, 34.25 mmol) was heated at 70° C. for 1 h and then concentrated in vacuo. 3-Amino-6-(1-phenylcyclopropyl)pyridine-2(1H)-thione (225 mg, 0.929 mmol) was added to the residue, and the resulting mixture was and heated in toluene (9.0 mL) at 100° C. for 10 min. (±)-10-Camphorsulfonic acid (194 mg, 836 μmol) was subsequently added, and the resulting mixture was heated at 100° C. for 30 min. The reaction solution was then cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-40% ethyl ether/hexanes) provided 2-(4-(benzyloxy)-3,5-dimethylphenyl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine as a white solid. MS (ESI) m/z: Calculated: 462.2; Observed: 463.2 (M++1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:46])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:43]([CH3:45])[CH3:44])[CH:30]([O:35][Si](C(C)(C)C)(C)C)[C:31]([F:34])([F:33])[F:32])=[O:27])[C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(NC1C(=O)N(CC(NC(C(C)C)C(O)C(F)(F)F)=O)C(C)=C(C2C=CC=CC=2)C=1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:46])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:43]([CH3:44])[CH3:45])[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[O:27])[C:15]([CH3:24])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccccc2)cc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(C(C)C)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: Cc1c(-c2ccccc2)cc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(C(C)C)C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)cc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)NC(C(=O)C(F)(F)F)C(C)C

Procedure:
Using a similar procedure to that described in Example 1.e., 2-(3-benzyloxycarbonylamino-6-methyl-2-oxo-5-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide was converted into 2-(3-benzyloxycarbonylamino-6-methyl-2-oxo-5-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide; chromatography solvent: chloroform:methanol (40:1); TLC: Rf =O.14, chloroform:ethyl acetate (20:1); MS: m/z=546(M+1).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[CH:28][CH:27]=1.[NH2:35][CH:36]([CH3:39])[CH2:37][OH:38]>>[OH:38][CH2:37][CH:36]([NH:35][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:28]=[CH:27][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:31][CH:30]=1)=[O:7])=[O:18])[CH3:39]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1
Reactant: CC(N)CO
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC(C)CO)N(C(=O)c2ccc(-c3ccccc3C)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′-methyl[1,1′-biphenyl]-4-carboxylic acid, and (2RS)-2-amino-1-propanol, the title compound was obtained in 88% purity by HPLC. MS(ESI+): m/z=410.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:25])[O:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:7][O:6]1)=[O:4].O[Li].O>O1CCCC1.CO.O>[CH3:25][C:5]1([C:3]([OH:4])=[O:2])[O:6][CH2:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH2:9][O:10]1
Reactant: COC(=O)C1(C)OCC(CCCCON=C(C)c2ccccc2)CO1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=NOCCCCC1COC(C)(C(=O)O)OC1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of. Methyl-2-methyl-5-[4-(1-phenyl-ethylideneaminooxy)-butyl]-[1,3]dioxane-2-carboxylate (prepared as per example 1) (1.38 g) in a mixture of tetrahydrofuran and methanol was added another solution of LiOH.H2O (332 mg) in water and the reaction mixture was stirred at ambient temperature for about 18 hours. Solvent was evaporated under reduced pressure, water was added to the residue, acidified with 1N HCl to pH 6 and extracted with ethyl acetate. The combined organic extract was washed with water, brine solution, dried over sodium sulphate and evaporated under reduced pressure. Crude product was chromatographed (flash) over silica-gel using 25% ethyl acetate in hexane as an eluent to obtain 1 g of pure product.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=C[CH:3]=1.[NH2+:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:3][CH:2]1[C:17]2[CH:18]=[CH:19][C:20]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:21][C:16]=2[O:9][C:1]1=[O:8]
Reactant: c1ccccc1
Reactant: C1CC[NH2+]C1
Reactant: O=C([O-])c1ccccc1
Solvent: O
Product: CC1C(=O)Oc2cc(N3CCCC3)ccc21

Procedure:
A mixture of 18.2 g (0.1 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 20.3 g (0.105 mole) of pyrrolidinium benzoate in 400 ml of benzene is heated under reflux for 24 hours using a water separator. The benzene is then removed in vacuo and the residue that remains is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation from ether. Subsequent recrystallisation from ether/petroleum ether yields 3-methyl-6-(pyrrolidin-1-yl)-benzofuran-2(3H)-one having a melting point of 101°-103° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][Cl:20])=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[O:33][CH2:34][CH2:35][NH2:36]>CO>[ClH:20].[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([O:16][CH2:17][CH:18]([OH:21])[CH2:19][NH:36][CH2:35][CH2:34][O:33][C:32]2[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=[C:30]([O:29][CH3:28])[CH:31]=2)=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH2:11][CH2:10]2)[C:2]#[CH:3]
Reactant: COc1cc(OC)cc(OCCN)c1
Reactant: C#CCOc1ccc(OCC(O)CCl)c2c1NC(=O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCOc1ccc(OCC(O)CNCCOc2cc(OC)cc(OC)c2)c2c1NC(=O)CC2
Product: Cl
Reaction time: 8 h
Yield: 24.4 %

Procedure:
1.0 g of 8-(2-propynyloxy)-5-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril was dissolved in 30 ml of methanol. 0.5 g of anhydrous potassium carbonate and 1.4 g of 2-(3,5-dimethoxyphenoxy)ethylamine were added to the solution, and the resulting mixture was refluxed while stirring for 8 hours. The methanol was evaporated under reduced pressure, and the residue was rendered acidic with hydrochloric acid followed by washing with ethyl acetate. The hydrochloric acid layer was separated, extracted with chloroform, washed with water and dried over anhydrous sodium sulfate. The chloroform was evaporated under reduced pressure, and the residue was recrystallized from methanol-diethyl ether to obtain 0.4 g of 8-(2-propynyloxy)-5{3-[2-(3,5-dimethoxyphenoxy)ethylamino]-2-hydroxypropoxy}-3,4-dihydrocarbostyril hydrochloride having a melting point of 187°-189° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[CH2:28]([NH2:31])[CH2:29][NH2:30]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:30][CH2:29][CH2:28][NH2:31])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NCCN
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H cyclopenta[d]pyrimidine (0.5 g, 1.77 mmol) in acetonitrile (5 mL) was added diisopropylethylamine (0.343 g, 2.659 mmol) followed by ethane-1,2-diamine (0.138 g, 2.30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 10% methanol in chloroform) to get the title compound N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)ethane-1,2-diamine (0.35 g, 64.5%) as a dark brown solid. LC-MS (M+H)+=307.2. 1H NMR (400 MHz, CDCl3) δ ppm 7.11-7.08 (2H, m), 6.99-6.95 (2H, m), 5.40 (1H, br s), 4.25-4.22 (1H, m), 3.61-3.57 (2H, m), 2.99-2.98 (2H, m), 2.78-2.62 (3H, m), 2.10-2.09 (1H, m).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)cc1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.96 min, MH+ 402. NMR: δH [2H6]-DMSO 10.38,(1H, s), 9.20,(1H, s), 8.49,(1H, d), 8.40,(1H, dd), 7.91,(1H, s), 7.82,(1H, d), 7.76, (1H, d), 7.71,(2H, d), 7.43,(1H, d), 6.96,(2H, d), 3.76,(3H, s), 2.87,(1H, m), 2.40, (3H, s), 0.70,(2H, m), 0.58,(2H, m).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26]>>[CH3:26][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)[CH3:24]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CN(C)Cc1ccc(N)cc1
Product: CC/C(Nc1ccc(CN(C)C)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[NH:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[NH:26]1[CH:25]=[C:24]([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[NH:5][C:4]=3[CH:3]=2)[CH:28]=[N:27]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C1NC2(CCCC2)Nc2cc(Br)sc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1NC2(CCCC2)Nc2cc(-c3cn[nH]c3)sc21
Yield: 27.4 %

Procedure:
A mixture of 3-amino-5-bromothiophene-2-carboxamide (0.072 g, 0.33 mmol) and p-toluenesulfonic acid monohydrate (0.013 g, 0.066 mmol) in cyclopentanone (2 mL) and acetic acid (1 mL) was stirred at 70° C. for 2 h. Then, the reaction mixture was cooled, carefully poured into sat. NaHCO3 (50 mL), and extracted with 2:1 ethyl acetate/tetrahydrofuran (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to give crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a brown gum (0.174 g), which was used without further purification. A mixture of the crude 6′-bromo-1′H-spiro[cyclopentane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one (0.172 g), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.349 g, 1.80 mmol), 2 M sodium carbonate (1.2 mL, 2.4 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (0.073 g, 0.090 mmol) in 1,4-dioxane (3 mL) was microwave-irradiated at 140° C. for 1 h. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol), and purified again by flash chromatography (Combiflash, silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give the title compound (0.045 g, 2 step yield 50%) as a yellow solid:
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>C1COCC1>[CH3:9][C:7]1[CH:8]=[C:3]([B:11]([OH:16])[OH:12])[CH:4]=[C:5]([CH3:10])[CH:6]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Magnesium turnings (1.44 g, 59.43 mmol) were coverd with dry THF (18.8 mL) in a dried, nitrogen filled flask fitted with an addition funnel and reflux condenser. To this was added 5-bromo-m-xylene (10 g, 54.03 mmol) in THF (15 mL) after initiation of the Grignard reaction. The addition was carried out over several minutes and the reacton mixture was heated at reflux for 1-2 hours until most of the magnesium had reacted. The reaction mixture was then cooled and transferred to an addition funnel fitted to an nitrogen filled flask containing triisopropyl borate (24.9 mL) at −70° C. The dropwise addition was carried out over several minutes and the mixture warmed to room temperature and stirred overnight. The grey solution was poured onto 2 M HCl and immediately turned yellow. The solution was extracted with Et2O and the Et2O fractions were combined, dried over MgSO4 and the solvent was removed in vacuo to provide the desired product (2.41 g): m.p.249-251° C.; 1H NMR (CDCl3) d 2.44 (6H, s), 7.23 (1H, s), 7.84 (2H, s); 13C NMR (CD3OD) d 21.36, 133.28, 134.39, 137.48.