Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:20][OH:21].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:21][NH:20][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCN(CCO)CC2)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(CCO)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 15c (125 mg, 0.461 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (320 mg, 4.61 mmol) and a freshly prepared solution of sodium methoxide in methanol (159 mg, 6.91 mmol of sodium dissolved in 1.5 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 16c.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH3:15])[C:11]1=O>>[CH3:15][N:12]1[CH2:13][CH2:14][CH:10]([CH2:9][CH2:8][OH:7])[CH2:11]1
Reactant: CN1CCC(CCO)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1CCC(CCO)C1
Yield: 52.9 %

Procedure:
Lithium aluminium hydride (347 mg) was cautiously added, in portions, to a vigorously stirred suspension of 3-(2-hydroxyethyl)-1-methyl-2-pyrrolidinone (886 mg) in dry, freshly distilled tetrahydrofuran (60 ml), at 5° under nitrogen. The resultant suspension was stirred and heated at reflux under nitrogen for 1 h. The mixture was cooled to 5°, with stirring, and cautiously treated with a mixture of water (1 ml) and tetrahydrofuran (10 ml). The solvents were evaporated, the residue dissolved in ethanol and the solvent was again removed, in vacuo. The residue was chromatographed using dichloromethane:ethanol:ammonia (25.8:1) as eluent, to give the title compound (423 mg).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][N:6]1[CH2:10][CH2:9][C:8](=[O:11])[C:7]1=[O:12]>O>[CH3:5][N:6]1[CH2:10][C:9](=[N:1][OH:3])[C:8](=[O:11])[C:7]1=[O:12]
Reactant: O=N[O-]
Reactant: CN1CCC(=O)C1=O
Agent: [Na+]
Solvent: O
Product: CN1CC(=NO)C(=O)C1=O
Reaction time: 2 h
Yield: 56.3 %

Procedure:
10.5 g (0.15 mol) of sodium nitrite in 50 ml of water are added dropwise at 0° C. to a solution of 17.0 g (0.15 mol) of 1-methyl-2,3-pyrrolidinedione (H. Rapoport et al., J. Org. Chem. 40 (1975) 1264). The mixture is stirred for a further 2 hours, the deposited product is filtered off and 12.0 g (58%) of 1-methyl-2,3,4-pyrrolidinetrione-4-oxime are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH2:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>CC1C=CC(C)=CC=1>[CH2:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:3]=[CH:4][N:5]=[C:6]([Cl:8])[CH:7]=2)[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1cc(Cl)ncn1
Solvent: Cc1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCN(Cc3ccccc3)CC2)ncn1
Temperature: 138 °C
Reaction time: 18 h

Procedure:
A mixture of 4,6-dichioropyrimidine (29.5 g), N-benzylpiperazine (44.0 g) and DIPEA (44 ml) was suspended in p-xylene (400 ml) and heated at 138° C. under reflux. After 18 hours the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was evaporated using high vacuum pump apparatus to obtain 1-(benzyl)-4-(4-chloropyrimidin-6-yl)piperazine a brown solid, 60.5 g (105% based on 4,6-dichloropyrimidine);
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]#[N:10])=[N:5][C:4]=1[N+:11]([O-:13])=[O:12].C(OCC)(=[O:16])C>OS(O)(=O)=O.O>[Br:1][CH2:2][C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:10])=[O:16])=[N:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: Cn1c(C#N)nc([N+](=O)[O-])c1CBr
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(N)=O)nc([N+](=O)[O-])c1CBr
Yield: 84 %

Procedure:
A solution of 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carbonitrile (264) (70 mg, 0.29 mmol) in 90% H2SO4 (1 mL) was heated at 65-70° C. for 1 hour, before being diluted with water and given a standard ethyl acetate workup to give 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole-2-carboxamide (266) (67 mg, 84%), as white solid, m.p. 220-222° C. 1H NMR [(CD3)2SO] δ 8.18 (s, 1H), 7.87 (s, 1H), 5.05 (s, 2H), 4.02 (s, 3H). HR-MS (APC+, 79/81Br) found: m/z 262.9770/264.9752 (M+1), calcd. for C6H879/81BrN4O3+: 262.9774/264.9754.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([C:20](=[O:31])[C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=3[F:30])=[CH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:19][C:17]1[C:16]([C:20]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=2[F:30])=[O:31])=[CH:15][N:14]=[C:13]([NH:12][CH:10]2[CH2:11][NH:8][CH2:9]2)[N:18]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CN(C(=O)OC(C)(C)C)C2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CNC2)nc1N
Reaction time: 2 h

Procedure:
To a stirred suspension of the protected amine (940 mg, 2.16 mmol, Example 319) in methylene chloride (30 mL), trifluoroacetic acid (20 mL) was added at 0° C. and the mixture stirred for 2 hours. The solvent was removed and the residue was partitioned between ethyl acetate and 5% sodium carbonate solution. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (1:1, 3×10 ml). The extracts were combined and the solution was dried with sodium sulfate. Removal of solvent gave a yellow solid. 711 mg, 98%. MS (ES) MH+=336.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.O>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:15]([CH:12]3[CH2:14][CH2:13]3)=[O:16])[N:10]=2)[N:7]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution (10 mL) of 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol) in N,N-dimethylacetamide was added cyclopropylcarbonyl chloride (0.38 mL, 4.23 mmol), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate (4/1) to give the title compound (1.01 g, 80%) as a dark brown powder.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: C#Cc1cccc(C#N)c1
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: N#Cc1cccc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and the product of Example 19A (64 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (t, J=7.8 Hz, 1H), 7.94 (s, 1H), 8.04 (dt, J=7.8, 1.4 Hz, 1H), 8.25 (dt, J=8.1, 1.4 Hz, 1H), 8.42 (t, J=1.5 Hz, 1H), 9.32 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][C:25]2=[O:28])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Si:1]([O:18][C:19]1[CH:27]=[C:26]2[C:22]([CH2:23][CH2:24][CH:25]2[OH:28])=[CH:21][CH:20]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1ccc2c(c1)C(=O)CC2)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](Oc1ccc2c(c1)C(O)CC2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-tert-butyldiphenylsilyloxy-1-indanone, as described above in Step A, (16.5 g, 42.7 mmol) in MeOH (500 mL) was added NaBH4 (3.2 g, 84.6 mmol) portionwise, over 5 min. The resulting mixture was stirred at ambient temperature for 1 hour, then cooled to 0° C. The chilled solution was adjusted to pH 4.5 with dilute aqueous HCl, then most of the MeOH was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (75 mL) and CHCl3 (150 mL). The organic layer was removed, and the aqueous phase was extracted further with CHCl3 (2×100 mL). The combined organic extracts were washed with brine, then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane—10% to EtOAc, to yield the titled product.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:14])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.O=S(Cl)Cl.Cl.[CH3:20][O:21][C:22](=[O:25])[CH2:23][NH2:24]>>[C:22]([CH2:23][NH:24][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH3:14])[C:2]=1[Cl:1])=[O:13])([O:21][CH3:20])=[O:25]
Reactant: Cn1c(Cl)c(C(=O)O)c2ccccc21
Reactant: COC(=O)CN
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)c1c(Cl)n(C)c2ccccc12
Yield: 78 %

Procedure:
Similar reaction of 2-chloro-1-methylindole-3-carboxylic acid [XXI] with SOCl2 and glycine methyl ester hydrochloride gave N-carbomethoxymethyl 2-chloro-1-methylindole-3-carboxamide [XXII: R6 =H, R7 =CH2COOMe] (78% yield); mp (CHCl3 /light petroleum) 102.5°-104° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)CCN(C)C.[CH2:21]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>CCOCC.O.CCCCCC>[N:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:30])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=3[CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]2=3)=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2CCc2ccccc21
Reactant: Brc1ccncc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: OC1(c2ccncc2)c2ccccc2CCc2ccccc21
Temperature: -75 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
To a stirred solution of 4-bromopyridine (37.9 g, 0.24 mol) in anhydrous ether (475 mL) at -75° C. under a nitrogen atmosphere was added n-butyllithium (160 mL of a 1.5 M hexane solution, 0.24 mol). Tetramethylethyenediamine (36.2 mL, 0.24 mol) was added and the solution was stirred at -75° C. for 1 hour. A solution of dibenzosuberone (50.l g, 0.24 mol) in anhydrous ether (250 mL) was added dropwise, the reaction mixture was stirred at -75° C. for 40 minutes, warmed to ambient temperature and stirred at that temperature for 1.5 hours. Water (650 mL) was added dropwise. The solid which crystallized was isolated by filtration to give 43.54 g of 10,11-dihydro-5-(4-pyridinyl)-5H-dibenzo[a,d]cyclohepten-5-ol, mp 174-177° C. Recrystallization from ethyl acetate-hexane gave material of mp 183-185° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[C@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[NH2:15][CH2:14][C@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][C@H:10]1[OH:26]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN2C(=O)c3ccccc3C2=O)[C@H](O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)[C@H](O)C1
Yield: 110.8 %

Procedure:
To a solution of cis-l-tert-butoxycarbonyl-4-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)methyl-3-hydroxypiperidine (2.4 g) in ethanol (35 ml) was added hydrazine monohydrate (0.48 ml), and the resulting mixture was stirred at refluxing temperature for 1 hr. The resulting crystals were filtered off and the solvent was evaporated under reduced pressure to give 1.7 g of cis-4-aminomethyl-1-tert-butoxycarbonyl-3-hydroxypiperidine.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=1.[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:25]1[CH:35]=[CH:34][CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[C:26]=1[CH2:27][O:28]C(=O)C)[N:18]=[CH:17]2)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([C:25]1[C:26]([CH2:27][OH:28])=[C:32]([C:2]3[S:3][CH:4]=[C:5]([C:7]([NH2:9])=[O:8])[N:6]=3)[CH:33]=[CH:34][CH:35]=1)[N:18]=[CH:17]2)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Reactant: NC(=O)c1csc(Br)n1
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4nc(C(N)=O)cs4)c3CO)ncc2c1
Yield: 25 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 2-bromothiazole-4-carboxylic acid amide (intermediate-2) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (25% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.41 (s, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.05-8.00 (m, 2H), 7.82 (dd, J=1.8, 7.2 Hz, 1H), 7.61-7.58 (m, 2H), 4.54-4.45 (m, 2H), 1.41 (s, 9H). LC-MS calcd for C23H22N4O3S (m/e) 434.14, obsd 435 [M+1]+.
Reaction SMILES: Cl[Sn]Cl.Cl.[C:5]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:5]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)[NH2:17])([CH3:8])([CH3:7])[CH3:6]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2CNC(C)(C)C)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)cc2CNC(C)(C)C)CC1
Temperature: 25 °C
Yield: 49 %

Procedure:
A mixture of SnCl2 (0.364 g, 4 eq), 1.44 mL of HCl 1M and 5 mL of THF was added to a solution of tert-butyl({[2-(4-methylpiperazin-1-yl)-5-nitrophenyl]methyl})amine (0.147 g, 0.48 mmol) in 20 mL of THF. The reaction mixture was refluxed for 3 h and allowed to cool to room temperature. A saturated aqueous solution of Na2CO3 was added. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (DCM/MeOH/NH4OH//85/15/1) to yield expected compound as a brown oil (65 mg, 49% yield).
Reaction SMILES: C1C(C(N)=O)=CN(C2OC(C[O:16][P:17]([O:20][P:21]([O:24]CC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-:23])=[O:22])([O-:19])=[O:18])C(O)C2O)C=C1.[Na+:49].[Na+].[Na+].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].S(=O)(=O)(O)O.P(O)([O-])([O-])=O.[Na+].[Na+]>>[O-:18][P:17]([O:20][P:21]([O-:24])([O-:23])=[O:22])(=[O:16])[O-:19].[Na+:49].[Na+:49].[Na+:49].[Na+:49]
Reactant: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: O=P([O-])([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Product: O=P([O-])([O-])OP(=O)([O-])[O-]

Procedure:
Process as claimed in claim 13 for the production of tetrasodium pryophosphate, wherein trisodium orthophosphate is acidified with sulfuric acid, disodium orthophosphate is separated from the reaction mixture and the disodium orthophosphate so separated is heated to btween 400° C. and 600° C. to form tetrasodium pyrophosphate.
Reaction SMILES: B.O1CCCC1.[I:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)=[CH:10][CH:9]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[I:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: O=C1CCCN1c1ccc(I)cc1
Agent: B
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Ic1ccc(N2CCCC2)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
A mixture of borane-tetrahydrofuran complex (1.2 M in THF, 5.81 mL) and 1-(4-iodophenyl)pyrrolidin-2-one (1.00 g) in THF (dry) (20 mL) was stirred at 70° C. under N2 for 3 hr. The mixture was poured into 1N HCl aq., sat.NaHCO3 aq. was added and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (0.954 g) as a white solid.
Reaction SMILES: [C:1](O)(=[O:4])CC.[Cl:6][C:7]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:8]=1[CH2:9][NH:10][C:11](=[O:21])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Cl)[CH3:13]>>[Cl:6][C:7]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:8]=1[CH2:9][NH:10][C:11](=[O:21])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:4][CH3:1])[CH3:13]
Reactant: CCC(=O)O
Reactant: CC(C(=O)NCc1cccc(C(F)(F)F)c1Cl)c1ccccc1Cl
Product: COc1ccccc1C(C)C(=O)NCc1cccc(C(F)(F)F)c1Cl
Yield: 42 %

Procedure:
The titled compound was prepared from 22-methoxyphenyl)propionic acid in 42% yield in the same manner as the preparation of N-(2-Chloro-3-trifluoromethylbenzyl)-2-(2-chlorophenyl)propionamide in Example 184b. MS (ESI) 372 (MH+).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:10][CH:5]2[C:4]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:3]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].C(OC(C)C)(C)C>>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:22][CH2:21][C:17]1[CH:16]=[C:15]([CH2:14][NH:13][C:11]([N:9]2[CH2:8][CH2:7][N:6]3[C:2](=[O:1])[O:3][C:4]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:5]3[CH2:10]2)=[O:12])[CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNC(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: NCc1cccc(CNC(=O)N2CCN3C(=O)OC(c4ccccc4)(c4ccccc4)C3C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To 1,1-dimethylethyl [[3-[[[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]methyl]phenyl]methyl]carbamate (0.12 g, 0.22 mmol) was added trifluoroacetic acid (1.5 mL), and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added diisopropyl ether, the precipitated powder was collected by filtration and dried to obtain the title compound (0.11 g, yield 84%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:22][CH2:23][NH2:24]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][CH2:22][CH2:23][NH2:24])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCBr
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(N)cc1
Agent: Br
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(NCCN)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 56.3 %

Procedure:
A mixture of N-[4-(4-aminophenyl)butyl]carbamic acid tert-butyl ester (4.5 g, 17 mmol) and 2-bromoethylamine hydrobromide (1.75 g, 8.5 mmol) in toluene was stirred at 100° C. for 3 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 8:1:0.1, v/v) to give 660 (1.47 g, 56%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.51 (m, 4H), 2.48 (t, 2H), 2.85 (t, 2H), 3.03 (t, 2H), 3.17 (m, 2H), 6.59 (d, 2H), 6.94 (d, 2H). m/z (ESI) 308 [C17H29lN3O2+H].
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:11][CH:12]=[CH:13][Cl:14]>>[Cl:1][CH:2]([Cl:6])[C:3](=[O:4])/[C:13](/[Cl:14])=[CH:12]/[Cl:11]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: ClC=CCl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(/C(Cl)=C/Cl)C(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
At room temperature, dichloroacetyl chloride (50 g, 0.339 mol) was added dropwise (slightly exothermic) to a suspension of AlCl3 (45 g, 0.339 mol) in 1,2-dichloroethylene (49.3 g, 0.508 mol). The reaction mixture was stirred under reflux conditions for 3 h and then at room temperature overnight. The reaction mixture was then stirred into ice water (500 g) (foams and reacts violently) and extracted three times with methylene chloride (200 ml). The combined organic phases were washed once at 10° C. with a saturated aqueous NaHCO3 solution and dried over magnesium sulfate, and the solvent was removed at a bath temperature of 70° C. at atmospheric pressure. The residue was subjected to incipient distillation at 50 mbar and 70° C. This gives 46.5 g of a black oil having a (Z)-1,1,3,4-tetrachlorobut-3-en-2-one content of about 70% and contains 25% of a byproduct, which is (Z)-1,1,1,4-tetrachlorobut-3-en-2-one. Accordingly, the yield of (Z)-1,1,3,4-tetrachlorobut-3-en-2-one is 38%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31][N:48]4[CH2:49][CH2:50][CH:45]([OH:44])[CH2:46][CH2:47]4)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC1CCNCC1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC(O)CC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 from cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol of Example 124, p-toluenesulfonyl chloride and 4-hydroxypiperidine (Fluka, Buchs, Switzerland). Analytical HPLC-MS: tR=1.49 min; ES-MS: m/eo=512.48.
Reaction SMILES: [CH:1]([N:14]1[CH2:17]C(C#N)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl.[Cl-].[Na+].C[O:26][CH:27]([OH:29])[CH3:28]>O>[CH:1]([N:14]1[CH2:17][CH:28]([C:27]([OH:29])=[O:26])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(C)O
Reactant: N#CC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 1-benzhydryl-3-cyanoazetidine (5.43 g) in methoxyethanol (54 ml) were added potassium hydroxide (6.48 g) and water (3.25 ml), followed by stirring at 100° C. for 4 hr. The reaction mixture was allowed to cool down to room temperature. The reaction mixture was poured into ice. After adjusting this to pH 5 with 1N hydrochloric acid, sodium chloride was added thereto. This was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure to provide a crude product of the titled compound as pale yellow crystals. The crystals were suspended by addition of diethyl ether (15 ml). The crystals were collected by filtration and washed with diethyl ether. This was dried under aeration to provide the titled compound as pale yellow crystals (4.20 g, 71.7%).