Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: S=C1CCc2c(ccc(Br)c2Cl)N1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1ccc(Br)c(Cl)c1CC2
Temperature: 120 °C

Procedure:
To a stirred solution of 6-bromo-5-chloro-3,4-dihydroquinoline-2(1H)-thione (143-6; 0.3 g, 0.0012 mol) in n-butanol (10 mL) was added acetic hydrazide (0.2 g, 0.00213 mol). Reaction mass was heated at 120° C. for 16 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 298.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=CC=1)[NH:7]C=[CH:5]2.C([O-])([O-])=O.[K+].[K+].IC.[CH3:19][N:20]1[C:24](=O)[CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH3:19][N:20]1[C:24]2[C:23](=[CH:5][C:4]([C:8]#[N:7])=[CH:3][CH:2]=2)[CH:22]=[CH:21]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C#N)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A mixture of 5-bromoindole (500 mg; 2.55 mmol) and cuprous cyanide (342 mg; 3.83 mmol) in NMP (10 mL) was heated under microwave irradiations to 100° C. for 30 minutes then at 200° C. for 30 minutes. The reaction mixture was partitioned with water and DCM and the organic layer was washed with brine and concentrated in vacuo to give a pink solid. Purification by silica column chromatography (DCM) gave a white solid. It was dissolved in DMF (5 mL) and K2CO3 (704 mg; 5.10 mmol) and iodomethane (543 mg; 3.83 mmol) were successively added. The reaction mixture was stirred at RT for 3 days and then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give a slightly yellow oil which crystallized upon standing to give the title compound as an off-white solid (80 mg, 70%). LC/MS (Method A): 156.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:1]2[C:12](=[O:13])[C:11]3[N:9]([CH3:10])[CH:8]=[N:7][C:6]=3[N:4]([CH3:5])[C:2]2=[O:3])=[CH:17][CH:16]=1
Reactant: Clc1ccc(OCCCCCCBr)cc1
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Product: Cn1cnc2c1c(=O)n(CCCCCCOc1ccc(Cl)cc1)c(=O)n2C
Yield: 61 %

Procedure:
Theobromine and 6-(4-chlorophenoxy)hexyl bromide were reacted and treated in substantially the same manner as described in Example 9(a) to give 6-(4-chlorophenoxy)hexyltheobromine (61%).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][N:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:23].C(N(CC)CC)C>C(O)C>[C:15]1(=[O:23])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][N:14]1[CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2CN1CCBr
Reactant: Sc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2CN1CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.9 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (150 mg, 1 mmole) and 2-[2-(bromo)ethyl]isoindolin-1-one (240 mg, 1 mmole) in ethanol (15 ml) was added triethylamine (0.21 ml, 1.5 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 2 hours. After the solvent was distilled off, chloroform was added to the residue which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethyl acetate/ethanol (15:1)] to obtain 238 mg of the desired product (77.0%, light brown solid).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.Cl.[NH2:24]O.O>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:24][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccccc3C)cnc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccccc4C)c3cnc21
Yield: 44.1 %

Procedure:
4-Chloro-1-ethyl-5-(2-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (5.40 g) was refluxed for 2 hours in 300 ml of glacial acetic acid containing 10 ml of concentrated hydrochloric acid and 10 g of hydroxylamine hydrochloride. At the end of this time the reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed four times with water and once with saturated sodium bicarbonate solution. It was then evaporated and chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane) to give 2.21 g of product, mp 168°-170°. This product was recrystallized from ethyl acetate together with the product of another run to give analytically pure material, mp 170°-171° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([CH3:7])[CH3:6])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:9])[C:5]([CH3:7])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH3:10])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccccc1C
Temperature: 100 °C

Procedure:
To a mixture of 2-bromo-2-methylpropionic acid ethyl ester (8.27 mL, 64.0 mmol) and 2-methylphenol (7.60 g, 70.2 mmol) in dioxane (100 mL) was added Cs2CO3 (31.3 g, 96.0 mmol). After the mixture was refluxed at 100° C. for 4 hours and allowed to cool down to room temperature, the solvent was evaporated under reduced pressure. The residue was dissolved in Et2O, washed with 1 N NaOH, dried, and concentrated to give 9.69 g (68%) of D1a; 1H NMR (300 MHz, CDCl3) δ 7.13 (d, J=7.3 Hz, 1 H), 7.03 (t, J=7.6 Hz, 1 H), 6.87 (t, J=7.3 Hz, 1 H), 6.66 (d, J=8.2 Hz, 1 H), 4.24 (q, J=7.1 Hz, 2 H), 2.23 (s, 3 H), 1.59 (s, 6 H), 1.25 (t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:28]=1[O:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>>[F:43][C:40]1[CH:41]=[CH:42][C:27]([CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:24])=[C:28]([O:29][CH2:30][C:31]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[O:32])[CH:39]=1
Reactant: NCc1ccc(F)cc1OCC(=O)N1CCOCC1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1OCC(=O)N1CCOCC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 131, 2-(2-(aminomethyl)-5-fluorophenoxy)-1-morpholinoethanone. 1H NMR (CDCl3, 500 MHz) δ ppm: 1.59 (6H, s, gem-Me), 3.38, 3.54 (4H, br, NCH2), 3.62 (4H, m, OCH2), 3.96 (2H, m, NCH2), 4.01 (2H, m, OCH2), 4.55 (2H, s, OCH2), 4.55 (2H, d, J=4.3 Hz, NCH2), 5.17 (2H, s, OCH2), 6.53 (1H, dd, J=10, 2.1 Hz, Ar—H), 6.63 (1H, dt, J=2.5, 8 Hz, Ar—H), 7.23–7.26 (1H, m, Ar—H), 7.28–7.30 (3H, m, Ar—Hs), 7.42–7.44 (2H, m, Ar—Hs), 8.00 (1H, t, J=5.5 Hz, NH); 13C NMR (CDCl3, 125.77 Hz) δ ppm: 27.74, 38.76, 42.30, 42.98, 45.38, 58.06, 66.55, 66.78, 66.91, 74.72, 76.27, 100.40, 100.61, 108.07, 108.23, 122.56, 128.37, 128.49, 128.84, 130.88, 130.96, 139.69, 141.36, 141.98, 156.70, 157.02, 157.10, 159.58, 162.04, 163.99, 162.86, 165.79. HRMS (ESI) calcd for C30H34N4O7F (M+H) 581.2412. Found 581.2393.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[NH:11][C:10]=2[CH3:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:18]([O-:20])=[O:19])[N:11]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]=2[CH3:21])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]c2cccc([N+](=O)[O-])c2c1Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c([N+](=O)[O-])cccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indole (3.76 kg, 11.8 mol) and potassium carbonate (1.80 kg, 13.0 mol) were suspended in acetonitrile (32.7 kg). Water (0.53 kg) and a solution of ethyl bromoacetate (2.17 kg, 13.0 mol) in acetonitrile (5.75 kg) were added followed by an acetonitrile line rinse (2.97 kg). The mixture was heated at 50° C. for 6 hours then allowed to cool to 20° C. and held at this temperature overnight. Water (35.4 kg) was added to the reaction mixture and stirring continued for 30 minutes at 15° C. The solid product was collected by filtration, washed with acetonitrile (2.95 kg) then dried in a vacuum oven at 40° C. to afford [3-(4-chlorophenylsulfanyl)-2-methyl-4-nitro-1H-indol-1-yl]acetic acid, ethyl ester as a bright yellow solid, 4.33 kg (91%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](Cl)=[O:8])[CH:2]=1.[NH2:10][C:11]1[CH:12]=[C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:17][C:16]1[CH:15]=[CH:14][C:13]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[CH:12][C:11]=1[NH:10][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:8]
Reactant: O=C(Cl)c1cccnc1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Product: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(NC(=O)c3cccnc3)c2)cc1
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 2, pyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)4-cyanobenzamide to give the title compound in 67% yield; NMR Spectrum: (DMSOd6) 7.57 (d, 1H), 7.59 (m, 1H), 7.73 (d, 1H), 8.01 (d, 2H), 8.10 (m, 3H), 8.34 (d, 1H), 8.79 (d, 1H), 9.15 (d, 1H), 10.33 (s, 1H), 10.66 (s, 1H); Mass Spectrum M+H+ 377.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][C:7]1=[O:12].Br[CH2:14][C:15]1[C:16]([CH3:22])=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1.Cl>C1COCC1.O>[Cl:21][C:18]1[N:17]=[C:16]([CH3:22])[C:15]([CH2:14][O:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][C:7]2=[O:12])=[CH:20][CH:19]=1
Reactant: O=C1COCCN1CCO
Reactant: Cc1nc(Cl)ccc1CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(Cl)ccc1COCCN1CCOCC1=O
Temperature: 0 °C

Procedure:
Sodium hydride (190 mg of a 60%, 4.76 mmol) was suspended in THF (12.2 mL) and cooled to 0° C. 4-(2-Hydroxyethyl)morpholin-3-one (230 mg, 1.59 mmol) was added and the slurry was stirred for thirty minutes at 0° C. 3-(Bromomethyl)-6-chloro-2-methylpyridine (Example 421 Step 2) (350 mg, 1.59 mmol) was added and the solution was heated to 50° C. overnight. The reaction mixture was then cooled to ambient temperature, diluted with water, acidified using 1 N aqueous hydrochloric acid, and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (0-2% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]2)=O)[CH2:14][CH2:13]1)=O)C.O>C(OC)(C)(C)C>[F:25][C:23]([F:24])([F:26])[C:20]1([CH2:18][N:15]2[CH2:14][CH2:13][CH:12]([CH2:10][OH:9])[CH2:17][CH2:16]2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)C1CCN(C(=O)C2(C(F)(F)F)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: COC(C)(C)C
Product: OCC1CCN(CC2(C(F)(F)F)CC2)CC1
Reaction time: 0.17 h
Yield: 96.1 %

Procedure:
Lithium aluminum hydride (208 g, 5.0 eq) is suspended in 3.9 L of methyl tert-butyl ether and the suspension is stirred for 10 min. A solution of 1-(1-trifluoromethyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl ester (260 g, 0.93 mol) in 1.3 L of methyl tert-butyl ether is added dropwise at <30° C. The mixture is refluxed for 20 h and cooled to 0˜10° C. 500 mL of water are added at 0˜10° C. and the mixture is stirred for 30 min. The suspension is filtered and the cake is washed with 1.8 L of methyl tert-butyl ether. The filtrate is concentrated to ˜3 L of volume at <35° C. under vacuum. The solvent is displaced with tetrahydrofuran (1.0 L×2) and concentrated to provide 212 g of the title compound in 96.8% purity.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][C:10]1=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36](Cl)=[O:37])[N:24]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:25]([CH2:35][C:36]([N:12]3[CH2:13][CH2:14][N:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[C:10](=[O:15])[CH2:11]3)=[O:37])[N:24]=2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: O=C1CNCCN1c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCN(c2ccccn2)C(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.6 %

Procedure:
160 mg 1-pyridin-2-yl-piperazin-2-one dihydrochloride was added to 216 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl chloride and 300 μL triethylamine in 10 mL dichlormethane. The reaction was stirred for 1 day at RT, the solvent was evaporated and the residue was purified by HPLC to yield 93 mg of the desired product.
Reaction SMILES: [CH:1](C1CC(=O)OC1=O)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([CH:24]1[CH2:29][C:28](=[O:30])[NH:27][C:25]1=[O:26])=CCCCCCC.[NH2:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][NH:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][NH2:43]>O.C(O)(C)C>[CH:1]([N:27]1[C:28](=[O:30])[CH2:29][CH2:24][C:25]1=[O:26])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38][NH:37][CH2:36][CH2:35][NH:34][CH2:33][CH2:32][NH2:31]
Reactant: CCCCCCC=CC1CC(=O)NC1=O
Reactant: CCCCCCC=CC1CC(=O)OC1=O
Agent: NCCNCCNCCNCCN
Solvent: O
Solvent: CC(C)O
Product: CCCCCCC=CN1C(=O)CCC1=O
Temperature: 142 °C

Procedure:
N-octenyl succinimide of tetraethylene pentamine was prepared by placing one mole of the amine in a reaction flask fitted with an additional funnel containing one mole of n-octenyl succinic anhydride, a water collector, a stirring the amine, the anhydride in the funnel was slowly added to the flask. Upon completion of the addition, the resulting reaction mixture was heated to about 142 degrees C. where water of reaction started to distill over. At about 180 degrees C., the resulting reaction product, viz., n-octenyl succinimide of tetraethylene pentamine, was a clear bright orange liquid. About one mole of water was collected in the collector signifying that the imide-forming reaction was complete. The flask and its contents were then cooled to about 80 degrees C. and sufficient isopropanol and distilled water were added to yield a solution which was: (i) 40 volume percent isopropanol, (ii) about 60 volume percent water and (iii) about 30 weight percent imide. Into this solution, based upon the total weight of the solution, about 1 weight percent mono-9-octadeceneoate of poly (oxy-1, 2-ethanedlyl) sorbitol (about 20 ethanediyl groups) surfactant was added to facilitate effective dispersion of the imide agent when added to cooling water. The flask and its contents were maintained at about 80 degrees C. with stirring until a clear solution resulted. The cooled solution was ready for use in accordance with the invention.
Reaction SMILES: [CH2:1]([C:4]1[C:17]2[O:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:18])[C:8]=2[C:7]([CH3:19])=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([C:37]([OH:38])=[O:40])[CH2:1][C:4]=2[C:17]2[O:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9](=[O:18])[C:8]=2[C:7]=1[CH3:19]
Reactant: C=CCc1c(O)c(Cl)c(C)c2c(=O)c3ccccc3oc12
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(Cl)c2c(c3oc4ccccc4c(=O)c13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
A mixture of 4-allyl-2-chloro-3-hydroxy-1-methyl-9-oxo-9H-xanthene (2.8 g), m-chloroperbenzoic acid (6.4 g) and chloroform (300 ml) was stirred at room temperature for 5 hours and thereafter left to stand overnight. To the mixture, potassium carbonate (20 g) and water (400 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (500 ml) and, to the stirred solution, a mixture of chromium trioxide (5 g), water (25 ml) and concentrated sulfuric acid (8 g) was added dropwise at room temperature. After standing overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 1.6 g of 4-chloro-1,2-dihydro-5-methyl-6-oxo-6H-furo[2,3-c]xanthene-2-carboxylic acid. m.p. 284°-287° C. This compound showed a mass spectrum having a molecualr ion peak at m/e 330.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35]>>[CH3:31][O:32][CH2:33][C:34]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A172) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[C:20](O)([CH3:23])([CH3:22])[CH3:21].CC(=C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:12]
Reactant: CC(C)(C)O
Reactant: Cc1ccccc1C(=O)CCC(=O)O
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)CCC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A mixture of 4-(2-methylphenyl)-4-oxobutanoic acid (40 g), concentrated sulphuric acid (4 mL) and t-butanol (4 mL) in dichloromethane (200 mL) is cooled to 0° C., and isobutylene (about 400 mL) is condensed into the mixture. It is then stirred at 0° C. until t.l.c. shows reaction is complete. The excess isobutylene is allowed to evaporate, and then the mixture is treated carefully with saturated aqueous sodium bicarbonate solution (200 mL), with vigorous stirring. The organic layer is separated, filtered through a pad of silica gel with the aid of more dichloromethane, and concentrated in vacuo, to give t-butyl 4-(2-methylphenyl)-4-oxobutanoate (5 g), in the form of a pale yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][CH2:7][C:8](Cl)=[O:9]>O.ClCCl.[OH-].[Na+]>[Cl:6][CH2:7][C:8]([NH:1][C@@H:2]([CH3:5])[CH2:3][OH:4])=[O:9]
Reactant: C[C@H](N)CO
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](CO)NC(=O)CCl
Yield: 82.2 %

Procedure:
To a stirred solution of (S)-2-aminopropan-1-ol (10 g, 0.13 mol) in water at 0° C. was added simultaneously a solution of chloroacetyl chloride (18 g, 0.16 mol) in dichloromethane (50 mL) and 1.6M aqueous sodium hydroxide (100 mL) dropwise over 1 h. The dichloromethane was removed under reduced pressure then the aqueous layer was extracted with ethyl acetate. The separated organic layer was dried (Na2SO4) and concentrated to afford (S)-2-chloro-N-(1-hydroxypropan-2-yl)acetamide (16.2 g, 83%) as a colourless oil which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:9]1([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[CH:18][C:17]([CH2:30][CH2:31][NH2:32])=[C:16]2[CH3:33])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]([NH:32][CH2:31][CH2:30][C:17]1[CH:18]=[C:19]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[N:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:16]=1[CH3:33])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1c(CCN)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC(=O)NCCc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccccc2)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TEA (0.29 g, 0.296 mmol) and acetoxyacetyl chloride (0.323 g, 0.00237 mol) are added, at 0° C., to a solution of 2-[1-phenyl-2-methyl-5-(4-methylsulphonylphenyl)-1H-pyrrol-3-yl]-ethanamine (W2008014821), (0.7 g, 0.00197 mol), in CH2Cl2 (10 mL). It is stirred at RT for 2 h. Then it is poured into water and extracted with CH2Cl2, washed with NaHCO3 s.s., and then with H2O, dried and concentrated. The solid obtained (0.85 g, 95.5%) is used as it is for the next step.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]5[CH2:28]CC[CH2:25]5)[CH:18]=4)=[CH:16][C:9]=23)[C:5]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[N:4]1)[CH3:2].[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37]>>[CH3:28][N:24]([CH2:23][C:19]1[CH:18]=[C:17]([C:15]2[NH:14][C:10]3=[N:11][CH:12]=[CH:13][C:8]([C:6]4[C:5]([C:29]5[CH:30]=[CH:31][C:32]([NH:35][C:39]([NH:38][CH2:36][CH3:37])=[O:40])=[CH:33][CH:34]=5)=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=4)=[C:9]3[CH:16]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:25]
Reactant: CCN=C=O
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN5CCCC5)c4)cc23)c(-c2ccc(N)cc2)n1
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)cc1

Procedure:
Following the procedure described in Example 48 using [4-(1-ethyl-4-{2-[3-(1-pyrrolidinylmethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazol-3-yl)phenyl]amine and ethyl isocyanate provided the title compound. ESMS [M+H]+: 534.5
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[CH2:13]1[O:24][C:23]2[CH:22]=[C:21]3[C:17]([C:18]([C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=4)=[CH:19][NH:20]3)=[CH:16][C:15]=2[O:14]1>>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C:10]([N:28]1[CH2:29][CH:30]=[C:25]([C:18]2[C:17]3[C:21](=[CH:22][C:23]4[O:24][CH2:13][O:14][C:15]=4[CH:16]=3)[NH:20][CH:19]=2)[CH2:26][CH2:27]1)=[O:12]
Reactant: O=C(O)C1Cc2ccccc2C1
Reactant: C1=C(c2c[nH]c3cc4c(cc23)OCO4)CCNC1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3cc4c(cc23)OCO4)CC1

Procedure:
Prepared from 9a and 5,6-methylenedioxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.