Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15].[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Br:32])[CH:30]=2)[CH:25]=[C:24]1B1OC(C)(C)C(C)(C)O1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.O>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Br:32])[CH:30]=2)[CH:25]=[C:24]1[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[N:5]=[N:4][C:3]=1[O:14][CH3:15])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1c(B2OC(C)(C)C(C)(C)O2)cc2ccc(Br)cc21
Reactant: COc1nnc(-c2ccncc2)cc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1nnc(-c2ccncc2)cc1-c1cc2ccc(Br)cc2n1C(=O)OC(C)(C)C
Yield: 96.2 %

Procedure:
1.075 g 4-Iodo-3-methoxy-6-pyridin-4-yl-pyridazine, 1.45 g 6-bromo-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indole-1-carboxylic acid tert-butyl ester, 4.48 g cesium carbonate, and 140 mg [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) complex with dichloromethane (1:1) are dissolved in a mixture of 30 mL dioxane and 8.8 mL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to reflux for 2 hours. After diluting with EtOAc, the organic phase is washed with water and brine, dried with MgSO4 and concentrated in vacuo. Purification on silica (Flashmaster, methylenechloride/MeOH) gives 1.59 g (96%) 6-bromo-2-(3-methoxy-6-pyridin-4-yl-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1.CO>[Ir].ClCCl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1NCCC1=Cc1ccc(F)cc1
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCCC1Cc1ccc(F)cc1
Yield: 99.5 %

Procedure:
This example describes the preparation of I where n=1 and R1=p-fluorophenyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (10 mg, 0.012 mmol) and 3-(p-fluorobenzylidene)-2-pyrrolidinone (250 mg, 1.3 mmol). Methanol (3 mL) and dichloromethane (3 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 MPa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-p-fluorobenzyl-2-pyrrolidinone (250 mg, 100%) as a white crystalline solid. Chiral HPLC analysis (Chiralpak OD, 95% heptane, 4.9% isopropanol, 0.05% trifluoroacetic acid, 0.05% n-hexylamine, 40° C.) indicated that conversion was 100% and the enantiomeric excess was 88%. 19F NMR δ −117.39; 13C NMR δ 26.92, 35.90, 40.44, 42.88, 115.44 (d, J=21 Hz), 130.58, 135.21, 161.77 (d, J=241 Hz), 179.72; 1H NMR: δ 1.83 (m, 1H), 2.15 (m, 1H), 2.66 (m, 2H), 3.11-3.32 (m. 3H), 6.47 (br s, 1H), 7.00 (m, 2H), 7.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]([CH3:17])([CH3:16])[C:14]#[N:15].[OH-].[Na+]>CC(C)=O.O>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([NH:12][C:13]([C:14]#[N:15])([CH3:17])[CH3:16])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CC(C)(N)C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 25 ml of acetone was cooled to -10°, and 2.5 grams of 2-amino-2-methylpropionitrile was added. With the reaction mixture at -10°, a solution of 1.3 grams of sodium hydroxide in 3.5 ml of water was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 30 minutes. The acetone was removed under reduced pressure; the residue was extracted with diethyl ether, and the extract was separated and dried over magnesium sulfate. The extract was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 3.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile; mp, 154°-158°.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]([CH3:28])([CH3:27])[C@H:9]2[NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([N+:24]([O-])=O)=[CH:19][CH:18]=3)=[O:14])=[CH:5][CH:4]=1)#[N:2]>[Pd].C1COCC1.CO>[NH2:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:13]([NH:12][C@H:9]1[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH2:7][C:8]1([CH3:28])[CH3:27])=[O:14])=[CH:23]2
Reactant: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H]1NC(=O)c1cc2cc(N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
A mixture of (R)—N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-nitro-1H-indole-2-carboxamide (200 mg, 0.534 mmol) (prepared as described in Example 8) and 10% Pd/C (80 mg) in 1:1 THF/MeOH (24 mL) was stirred at rt under H2, provided a H2 balloon, for 3 hr. The catalyst was removed by suction filtration, and the filtrate was concentrated under vacuum. The residue was diluted with ethyl acetate (50 mL), washed with brine (20 mL), and dried over anhydrous MgSO4. It was concentrated under vacuum, and the residue was applied to ISCO (12 g silica gel, 40-55% ethyl acetate/hexane) to afford the desired title product (106 mg, 58% yield) as a pale yellow solid. LCMS (M+H)=345.38. 1H NMR (500 MHz, DMSO-d6) δ: 11.1 (s, 1H), 8.33 (d, J=9.3 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.98 (s, 1H), 6.68 (s, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.35 (d, J=9.3 Hz), 4.60 (br. s, 2H), 2.86 (dd, J=23.6, 16.5 Hz, 2H), 1.20 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: O(C(O[CH2:11][C:12]1[N:16]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][C:24]([C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)=[CH:23][C:22]=2[CH3:34])[N:15]=[CH:14][N:13]=1)=S)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:11][C:12]1[N:16]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[C:22]([CH3:34])=[CH:23][C:24]([C:28]3[N:29]=[N:30][N:31]([CH3:33])[N:32]=3)=[CH:25][C:26]=2[CH3:27])[N:15]=[CH:14][N:13]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1COC(=S)Oc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1C
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 23.6 %

Procedure:
To a solution of 5-phenoxythiocarbonyloxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole (130 mg, 0.79 mmol) in 20 ml of toluene was added AIBN (130 mg, 0.79 mmol) and tributyltin hydride (3.2 g, 11 mmol) and the mixture was stirred at 75° C. for 6.5 h. The solvent was concentrated in vacuo and the residue was purified by silica column chromatography (13 cm column, ethyl acetate/hexane, 1/1-5/1; methylene chloride/acetone, 4/1-0/1) to afford 61 mg (19%) of 5-methyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole, m.p. 126°-128° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Sc1ccccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
Under nitrogen, N-chlorosuccinimide (5.34 g., 40 mmoles) was slurried in 50 ml. of carbon tetrachloride and the stirred mixture cooled in an ice-water bath. o-Chlorothiophenol (5.76 g., 40 mmoles), dissolved in 25 ml. of carbon tetrachloride, was added dropwise. The ice-water bath was removed and the reaction mixture stirred at room temperature for approximately 16 hours. The reaction was filtered, evaporated to an oil, taken up in hexane, refiltered and reconcentrated to yield o-chlorobenzenesulfenyl chloride (6.8 g., oil).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:16]([NH2:18])[CH3:17]>O1CCCC1>[CH2:16]([NH:18][C:2]1[CH:3]=[N+:4]([O-:15])[C:5]2[C:10]([C:11]=1[N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:17]
Reactant: CCN
Reactant: O=[N+]([O-])c1c(Br)c[n+]([O-])c2ccccc12
Solvent: C1CCOC1
Product: CCNc1c[n+]([O-])c2ccccc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Bromo-4-nitroquinoline-N-oxide (10 g, 0.037 mol) was dissolved in tetrahydrofuran (100 ml). To the solution, ethylamine (5.96 g, 70% in H2O) was added and the mixture was stirred at room temperature for 1 hour. Tetrahydrofuran was distilled off under vacuum from the whole reaction mixture and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried with anhydrous sodium sulfate. Upon isolation and purification by chromatography on a silica gel column using chloroform as a developing solvent, 3-ethylamino-4-nitroquinoline-N-oxide was obtained in an amount of 5.4 g (yield, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])=O>C(O)(=O)C>[NH:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:9]1[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14]
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)Nc1ccccc1N)c(=O)n2C
Solvent: CC(=O)O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1nc3ccccc3[nH]1)c(=O)n2C

Procedure:
350 mg of 1-[(2-amino-phenylaminocarbonyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine are refluxed in 3 ml glacial acetic acid for two hours. Then the reaction mixture is evaporated down, the flask residue is combined with 5 ml of 1 M sodium hydroxide solution and washed with methylene chloride. Then the aqueous phase is acidified with 1 M hydrochloric acid and extracted with methylene chloride. The combined extracts are evaporated down and chromatographed through a silica gel column with cyclohexane/ethyl acetate/methanol (6:4:0 to 5:4:1) as eluant.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]1.[ClH:14].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:16]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[Br-]>C(OCC)(=O)C.CO.C(Cl)Cl.C(#N)C>[ClH:14].[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[S:8][CH2:7]3)[CH2:28][CH2:29]2)=[N:16]1
Reactant: CC1(C)SCN(CCCCBr)C1=O
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: CC1(C)SCN(CCCCN2CCN(c3nsc4ccccc34)CC2)C1=O
Temperature: 95 °C
Reaction time: 21 h
Yield: 60 %

Procedure:
A mixture of 3-(4-bromobutyl)-5,5-dimethyl-4-thiazolidinone (3.50 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (3.70 g), K2CO3 (6.34 g), NaI (330 mg) and acetonitrile (175 mL) was heated at 95° C. (bath temperature) under nitrogen. After 21 hours, TLC analysis (silica gel, 5% MeOH/CH2Cl2) showed the absence of starting bromide and the presence of a major product, Rf =0.33. The reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture filtered. The filtrate was concentrated in vacuo to an oil which was triturated with ethyl acetate. The mixture was filtered again and the filtrate, after concentration, was chromatographed (Waters Prep 500, one silica gel column, 3% MeOH/CH2Cl2) to give 3.48 g of a viscous oil. The oil was dissolved in diethyl ether (500 mL), the solution filtered to remove a fluffy solid, and the filtrate acidified to pH=1 (hydrion paper) with an HCl/diethyl ether solution. The resultant salt (3.23 g) was recrystallized from ethanol/ethyl acetate yielding 2.29 g of white needles, mp 222°-227° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH:28]=O>>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][N:1]1[CH:2]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: O=Cc1nc2ccccc2s1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1nc2ccccc2s1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available benzo[d]thiazole-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 369.10 g/mol.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([O:15]C)[C:12]([O:17]C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[CH2:1]([S:8][C:9]1[NH:14][C:13](=[O:15])[C:12]([OH:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(SCc2ccccc2)nc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c(SCc2ccccc2)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a solution of 6-(benzylsulfanyl)-2,3-dimethoxypyridine (Intermediate 44, 0.2 g, 0.76 mmol) in dichloromethane (1 ml) was added a solution of boron tribromide in dichloromethane (1 M, 0.77 g, 3.1 mmol) at −5° C. and reaction was stirred for 1 hour at 0° C. The temperature was gradually allowed to rise to room temperature before the mixture was stirred for a further 1 hour at room temperature. Upon cooling to 0° C. water (10 ml) was added drop-wise and the resulting mixture was filtered and the solid was washed with water (2 ml) followed by ethyl acetate (5 ml) and dried under vacuum at 40° C. to yield 6-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (35 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[CH:13]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>CCOCC>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:19]([OH:21])=[O:20])=[CH:13][C:6]=2[C:7]=1[CH3:12]
Reactant: O=C=O
Reactant: Cc1c(CO)oc2ccc(Br)cc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(CO)oc2ccc(C(=O)O)cc12
Reaction time: 2 h

Procedure:
A solution of 5-bromo-2-hydroxymethyl-3-methylbenzofuran (Annalen, 1112, 1973) (1.93 g) in dry ether (50 ml) was added dropwise to a stirred solution of n-butyl-lithium (12.90 ml of 1.55M solution in hexane) in dry ether (50 ml) at 0° C. under an atmosphere of dry nitrogen. The mixture was stirred at 0° for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water. The aqueous layer was separated, washed with ether and acidified with concentrated hydrochloric acid. The solid was filtered off, washed with water, dried and crystallised from isopropanol/petrol (b.p. 80°-100°) to give 2-hydroxymethyl-3-methylbenzofuran-5-carboxylic acid (0.50 g), m.p. 220°-222°.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[Br:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([OH:22])=O.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]2[C:32]3[CH:40]=[C:39]([NH2:41])[N:38]=[CH:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:26][C:25]=1[C:42]([F:45])([F:44])[F:43].C(N(C(C)C)CC)(C)C>C1COCC1.CC(N(C)C)=O>[Br:16][CH2:17]/[CH:18]=[CH:19]/[C:20]([NH:41][C:39]1[N:38]=[CH:37][C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[C:25]([C:42]([F:45])([F:44])[F:43])[CH:26]=3)[C:32]=2[CH:40]=1)=[O:22]
Reactant: Nc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reactant: O=C(O)/C=C/CBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C/CBr)Nc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reaction time: 2 h

Procedure:
A stirred solution of DCC (633 mg, 3.07 mmol) in THF (2 mL) under nitrogen was treated with a solution of acid 9 (506 mg, 3.07 mmol) in anhydrous THF (2 mL) at 0° C. The mixture was stirred for 2 h, then treated with compound 168 (200 mg, 0.62 mmol) in DMA (2 mL) followed by di-iso-propylethylamine (DIPEA) (535 μL, 3.07 mmol), before being stirred for a further 3 h at 0° C. The resulting crude (E)-4-bromo-N-(4-(4-fluoro-3-(trifluoromethyl)phenylamino)pyrido[3,4-d]pyrimidin-6-yl)but-2-enamide thus formed was treated in situ with 40% aqueous dimethylamine (942 μL, 18.60 mmol) at 0° C. with stirring for 1 h. The mixture was then diluted with ethyl acetate (300 mL), then poured into a beaker of ice-water (600 mL), stirred for 10 min and then extracted with EtOAc. The combined organic extracts were washed with 2% cold aqueous Na2CO3, water and brine before being dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/MeOH (9:1). Recrystallization from CH2Cl2/diisopropyl ether then gave (2E)-4-(dimethylamino)-N-{4-[4-fluoro-3-(trifluoromethyl)anilino]pyrido[3,4-d]pyrimidin-6-yl}-2-butenamide (170) (175 mg, 65%) as a pale yellow solid, 170-172° C. 1H NMR [(CD)2SO] δ 10.93 (s, 1H), 10.42 (s, 1H), 9.04 (s, 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.24-8.28 (m, 2H), 7.56 (t, J=9.6 Hz, 1H), 6.88 (dt, J=15.4, 6.0 Hz, 1H), 6.53 (d, J=15.4 Hz, 1H), 3.10 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C20H18F4N6O.0.4CH2Cl2: C, 52.32; H, 4.05; N, 17.94%. found: C, 51.99; H, 4.28; N, 18.07%.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18](Cl)[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:15][CH:14]=1>CC(C)=O>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])=[CH:15][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C(=O)C(Cl)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
41.8 g (0.66 mole) of 1,2,4-triazole were dissolved in 300 ml of acetone. 93.4 g (0.72 mole) of anhydrous potassium carbonate were added to this solution, the suspension was heated to the boiling point and a solution of 156.5 g (0.6 mole) of 1-(4-chlorophenoxy)-1-chloro-3,3-dimethyl-butan-2-one in 150 ml of acetone was added dropwise at a rate such that the mixture boiled under reflux, without being heated. When the addition had ended, the mixture was heated under reflux for 15 hours in order to bring the reaction to completion; the resulting precipitate was then filtered off, washed with acetone and discarded. The filtrate was freed from solvent under a waterpump vacuum, the residue was taken up in 300 ml of toluene and the mixture was washed once with a solution of 10 g of 37% strength hydrochloric acid in 200 ml of water. The aqueous phase was separated off and discarded; the organic phase was washed with 500 ml of water and--after adding a further 400 ml of toluene--was stirred with a solution of 14.5 g of sodium hydroxide in 350 ml of water at room temperature for 6 hours. The organic phase was then separated off, washed with water until neutral and freed from solvent under a waterpump vacuum. 153.5 g (87% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-one of melting point 75°-76° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH:25]=O)[CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][CH2:25][CH2:24][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:11]1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reactant: O=CCCc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(CN2CCC(NCCCc3cccnc3)CC2)cc1Cl
Yield: 25.6 %

Procedure:
The title compound was prepared from 1-(3,4-dichlorobenzyl)piperidine-4-amine (free base 187 mg), 3-(3-pyridinyl)propanal (125 mg), sodium triacetoxyborohydride (70 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane (10 ml). Water was added, the mixture neutralised with sodium bicarbonate and the organic phase separated, dried and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (70 mg) as a colourless oil.
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([CH3:35])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH:23]([CH3:35])[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(O)CC1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(OC(c2ccccc2)c2ccccc2)CC1

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: NCc1ccco1
Reactant: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C(C)(C)Cc1ccc(CNCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 55 %

Procedure:
At room temperature, a solution of 1.00 g (3.81 mmol) of tert-butyl 3-(4-formylphenyl)-2,2-dimethylpropionate (Example I-3) and 0.37 g (3.81 mmol) of furfurylamine in 10 ml of dichloroethane is stirred for 30 min, 1.21 g (5.72 mmol) of sodium triacetoxyborohydride are added and the mixture is then stirred at room temperature for 22 h. 6 ml of sat. NaHCO3 solution and 10 ml of ethyl acetate are then added, the phases are separated, the aqueous phase is extracted 2× with ethyl acetate and the combined organic phases are dried over sodium sulphate. The solvent is removed under reduced pressure, and chromatographic purification on silica gel (cyclohexane→cyclohexane/ethyl acetate 10:1→2:1) then gives 720 mg (55%) of tert-butyl 3-(4-{[(2-furylmethyl)amino]methyl}phenyl)-2,2-dimethylpropionate.