Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:30][CH:31]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:27]=[N:28][C:29]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:30][CH:31]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1ccc(-c2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc(-c5ccccc5)nn4)cc3CC[C@@H]12
Yield: 48.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 3-chloro-6-phenylpyridazine (88 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 77 mg (49%) of the title compound as an amorphous solid. mp 199°-200°. FDMS: m/e=415. α[D]589 =+67.26 (c=0.63, chloroform).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[C:10]2[N:11]([C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[N:12]=1)(=O)=O.[O:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:13]1[N:11]2[N:12]=[C:7]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)[C:8]([S:26]([CH3:29])(=[O:27])=[O:28])=[C:9]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:24]#[N:25])[C:10]2=[CH:15][CH:14]=1)[CH3:17]
Reactant: OB(O)c1ccoc1
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(OS(=O)(=O)C(F)(F)F)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(-c3ccco3)nn12
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 27.8 %

Procedure:
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-2-yl trifluoromethanesulfonate (50.0 mg), 3-furylboronic acid (23.6 mg), dichlorobis(triphenylphosphine)palladium (3.71 mg), and 2 N sodium carbonate (44.8 mg in 0.2 mL of water) in dioxane was stirred for 20 minutes at 85° C. The mixture was partitioned between EtOAc and water, and the organic layer was washed with brine, dried, and evaporated. Preparative thin layer chromatography (EtOAc-hexane=1-1) afforded 3-[7-ethyl-2-(2-furyl)-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an orange solid (11.5 mg).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:11]([C@@H:13]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:14][C@H:15]([CH2:19][NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH2:29][CH2:30][CH2:31][O:32][CH3:33])[CH:16]([CH3:18])[CH3:17])=O.[Cl-].[NH4+]>C(OCC)C.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:32][CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]([NH:20][CH2:19][C@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][C@H:13]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:41])[CH3:39])[CH:11]=[CH2:1])=[O:34]
Reactant: COCCCOc1ccccc1C(=O)NC[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C[C@H](C[C@H](CNC(=O)c1ccccc1OCCCOC)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The mixture of 2.38 g of potassium bis(trimethylsilyl)amide in 50 ml of diethyl ether is cooled to 0° C., admixed with 4.04 g of methyltriphenylphosphonium bromide and stirred over 30 minutes. The solution of 1.70 g of tert-butyl (1(S)-formyl-3(S)-{[2-(3-methoxypropoxy)-benzoylamino]methyl}4-methylpentyl)carbamate in 20 ml of diethyl ether is added dropwise. The reaction mixture is stirred at room temperature over 1 hour and subsequently poured onto 1M ammonium chloride solution and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a slightly yellowish oil. Rf=0.36 (1:1 EtOAc-heptane); Rt=5.05 (gradient I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].Cl>C1COCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH2:22][C:23]([OH:25])=[O:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(c1cn(CC(=O)O)c2ccccc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
A suspension of ethyl 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetate (248 mg, 0.626 mmol) and LiOH (74.9 mg, 3.13 mmol) in THF/water 1/1 (10 ml) was stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate and carefully acidified by slow addition of 1N HCl (pH=1). The phases were separated and the aqueous layer was extracted with ethyl acetate; the combined organic layers were dried over Na2SO4 and evaporated to dryness to give 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-1H-indol-1-yl)acetic acid as a yellow solid (220 mg, 0.597 mmol, 95% yield). MS/ESI+ 369.1 [MH]+.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].C([O-])(O)=O.[Na+].[OH:10][C@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@:17]3([OH:32])[CH2:18][CH2:19][C@@H:20]2[CH:30]=O)[CH2:12]1>O1CCOCC1.O>[CH3:3][O:2]/[N:4]=[CH:30]/[C@H:20]1[CH2:19][CH2:18][C@:17]2([OH:32])[C@H:16]3[C@H:25]([CH2:24][CH2:23][C@:21]12[CH3:22])[C@:26]1([CH3:29])[C@@H:13]([CH2:12][C@@H:11]([OH:10])[CH2:28][CH2:27]1)[CH2:14][CH2:15]3
Reactant: CON
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CO/N=C/[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 36.7 %

Procedure:
To a suspension of 0.16 g of methoxylamine hydrochloride and 0.19 g of NaHCO3 in 12 ml of dioxane and 10 ml of water a solution of 0.50 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 6 ml of dioxane was added dropwise at room temperature. After 15 minutes the solution was diluted with water and extracted with chloroform; the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash-chromatography (SiO2) using cyclohexane/ethyl acetate 60/40; the fractions containing the rifle compound were collected and evaporated to dryness. The residue was ground with di-iso-propyl ether/ethanol to give 0.20 g of the title compound (I-aa), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:9][N:10](C)C)=[CH:4][CH:3]=1.O.NN.C([N:25](CC)CC)C>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:8]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:9][NH:10][N:25]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)s1)c1ccncc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Yield: 86.9 %

Procedure:
A mixture of 1-(5-chloro-2-thienyl)-3-(dimethylamino)-2-(pyridin-4-yl)prop-2-en-1-one (5.1 mmol), hydrazine hydrate (7.6 mmol) and triethylamine (7.6 mmol) in 25 mL ethanol was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel (dichloromethane:methanol 50:1 to 20:1) to afford 1.16 g 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (83% yield).
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([O:33]C1C=CC=CC=1)=O)(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:43]([NH2:47])[CH2:44][CH2:45][CH3:46]>C(OCC)(=O)C>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:40]=[CH:41][CH:42]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH:30][C:31]([NH:47][CH2:43][CH2:44][CH2:45][CH3:46])=[O:33])(=[O:29])=[O:28])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCN
Reactant: O=C(NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccccc2)c1
Yield: 67.5 %

Procedure:
A benzene (10 ml) solution containing 200 mg (0.40 mmol) of 3-benzyloxy-N-[2-[(phenyloxycarbonylamino)sulfonyl]phenyl]benzamide produced in Example 45 and 0.09 ml (0.88 mmol) of butylamine was heated under reflux for 2 hours. The reaction mixture was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 130 mg (yield: 68.0%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:32]1[CH:37]=[CH:36][C:35]([CH2:38]O)=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: OCc1ccncc1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccncc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
To a suspension of 4-bromo-2-(trifluoromethyl)phenol (8.00 g) in 1,4-dioxane (100 ml), triphenylphosphine (10.99 g) and 4-pyridylcarbinol (3.84 g) were added. Then diisopropyl azodicarboxylate (8.93 g) was dropwised and stirred at 20° C. for 18 h. The mixture was evaporated off the solvent, diethyl ether (100 ml) and iso-hexane (25 ml) were added and stirred at 20° C. for 2 h, stood for 3 days, filtered and washed with diethyl ether and iso-hexane. The filtrate was concentrated and purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1 to 1:1) to give 11.16 g red-orange oil as 4-((4-bromo-2-(trifluoromethyl)phenoxy)methyl)-pyridine (80% purity).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[S:10][C:9]([NH:11][C:12]3[C:13]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([CH3:28])([CH3:27])[CH3:26])=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]=2[C:29]([F:32])([F:31])[F:30])=[N:4][N:3]=[N:2]1.[CH3:33]N(CCCN=C(N)C1C=CC(C2NC(C3C=CC(C(N)=NCCCN(C)C)=CC=3)=CC=2)=CC=1)C>>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:13]1[C:12]([NH:11][C:9]2[S:10][C:6]([C:5]3[N:1]=[N:2][N:3]([CH3:33])[N:4]=3)=[C:7]([C:29]([F:31])([F:32])[F:30])[N:8]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1Nc1nc(C(F)(F)F)c(-c2nnn[nH]2)s1
Reactant: CN(C)CCCN=C(N)c1ccc(-c2ccc(-c3ccc(C(N)=NCCCN(C)C)cc3)[nH]2)cc1
Product: Cn1nnc(-c2sc(Nc3cccnc3Oc3ccccc3C(C)(C)C)nc2C(F)(F)F)n1

Procedure:
Example A133 was prepared from N-(5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine (Example 404) following the procedure described for Example A132.
Reaction SMILES: Br[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[C:3]([CH:8]=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=Cc1ncccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: COc1ccccc1-c1cccnc1C=O
Temperature: 90 °C
Yield: 63.2 %

Procedure:
A stirred solution of 3-bromo-pyridine-2-carbaldehyde (128 mg, 0.69 mmol) and 2-methoxybenzeneboronic acid (111 mg, 0.73 mmol) in a mixture of THF (0.75 mL), DME (2.0 mL) and 2M Na2CO3 (0.75 mL) was degassed with Ar for 15 minutes, after which Pd(PPh3)4 (41 mg, 0.034 mmol) was added and the heterogeneous mixture heated to 90° C. overnight. The reaction was quenched with brine (15 mL) and diluted with EtOAc (40 mL). The organic layer was separated, washed with brine (4×15 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (EtOAc/Hexanes, 80:20, then 70:30) gave 3-(2-methoxy-phenyl)-pyridine-2-carbaldehyde (93 mg, 63%) as a yellow solid. 1H NMR (CDCl3) δ 3.74 (s, 3H), 6.99 (d, 1H, J=8.3 Hz), 7.10 (t, 1H, J=7.5 Hz), 7.25 (dd, 1H, J=7.4, 1.7 Hz), 7.40-7.49 (m, 1H), 7.55 (dd, 1H, J=7.9, 4.8 Hz), 7.74 (dd, 1H, J=7.9, 1.8 Hz), 8.80 (dd, 1H, J=4.6, 1.5 Hz), 9.95 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:43])=[O:10])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (Intermediate 36B, 440 mg, 0.936 mmol) was taken up in DCM (9.32 ml). DMF (93 n1) was added and the reaction was cooled to 0° C. Oxalyl chloride (164 μl, 1.873 mmol) was added and the mixture was allowed to stir for 1 hr eventually reaching room temperature. The mixture was concentrated in vacuo and then further dried under high vacuum. The residue was carried forward without further purification. MS: [M+H]+ m/z 484 (Methyl ester formed LCMS, sample prepared in MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-])=O.BrC1C2C(Cl)=NC=NC=2N(C2CCCC2)C=1.[NH2:29][C:30]1[C:31]2[C:38](C(C3C=CC=C(N)C=3)=O)=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1>>[NH2:29][C:30]1[C:31]2[C:38]([C:8]([C:7]3[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=3)=[O:9])=[CH:37][N:36]([CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)[C:32]=2[N:33]=[CH:34][N:35]=1
Reactant: Nc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Clc1ncnc2c1c(Br)cn2C1CCCC1
Product: Nc1ccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)cc1

Procedure:
The title compound was prepared from 4-Nitrobenzoyl chloride and 5-Bromo-4-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine by procedures analogous to those described for the preparation of (4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-amino-phenyl)-methanone. MS: 322.3 (MH+); HPLC Rf: 4.45 min. (HPLC method 4).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[CH3:37][N:38]1[CH:42]=[C:41]([S:43](Cl)(=[O:45])=[O:44])[N:40]=[CH:39]1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]1[CH:3]=[C:2]([NH:1][S:43]([C:41]2[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=2)(=[O:45])=[O:44])[CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)c4cn(C)cn4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (150 mg, 0.278 mmol) (COMPOUND CCC4, STEP A) in 4 mL of THF cooled to 0° C. was added 1-methyl-1H-imidazole-4-sulfonyl chloride (100 mg, 0.556 mmol). A few crystals of 4-(dimethylamino)pyridine and diisopropylethylamine (53.9 mg, 0.417 mmol) were added. The resulting reaction mixture was stirred at 0° C. for 20 min, then heated to 70° C. for ca. 7.5 h. The reaction mixture was cooled to rt and partitioned between ethyl acetate and 1M aqueous HCl (added brine to improve the layer separation). The organic layer was concentrated under reduced pressure and triturated sequentially with Et2O, methanol, and CH2Cl2 to yield the N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methyl-1H-imidazole-4-sulfonamide. Mass spectrum (ESI) 682.0 (M+1).
Reaction SMILES: Cl.[CH:2]([N:15]1[CH2:18][C:17]([CH3:20])([OH:19])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.O>[CH3:28][S:29]([O:19][C:17]1([CH3:20])[CH2:18][N:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 14.8 %

Procedure:
To a slurry of 1-benzhydryl-3-methylazetidin-3-ol hydrochloride (10.00 g, 34.54 mmol) in dichloromethane (80 ml) was added triethylamine (8.00 g, 79.20 mmol) and the mixture cooled to 0° C. Methanesulfonyl chloride (5.20 g, 45.41 mmol) was added dropwise and the reaction mixture was then allowed to warm to room temperature and stirred for 4 hrs. The reaction was diluted with water and dichloromethane and the organic layer was washed further with water, brine then dried (MgSO4) and concentrated to give a pale pink solid. The solid was purified on silica gel eluting with 20% ethyl acetate/petrol to provide the title compound as a white solid (1.69 g, 64%). 1H NMR (CDCl3) 1.92 (3H, s), 3.05 (3H, s), 3.33 (4H, s), 4.42 (1H, s), 7.18-7.20 (2H, m), 7.23-7.30 (4H, m), 7.39-7.52 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1>C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:10](=[O:11])[NH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:13]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: OCc1cccnc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)OCc2cccnc2)cc1
Temperature: 100 °C

Procedure:
A resealable tube was charged with 4-methoxyphenylisocyanate (1.00 g, 6.70 mmol), 3-pyridylcarbinol (0.800 g, 7.33 mmol), and toluene (4 mL). The tube was sealed and the mixture was heated at 100° C. for 20 h. The reaction mixture was cooled to room temperature. The resulting white solid was collected by suction filtration and washed with diethyl ether. The solid was dried under vacuum to give (4-methoxyphenyl)-carbamic acid pyridin-3-ylmethyl ester a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:3]=1[NH2:16].[C:17](OCC)(OCC)(OCC)[CH2:18][CH3:19].C(S(O)(=O)=O)C>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:16]=[C:17]([CH2:18][CH3:19])[N:8]2[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: Nc1c(Cl)ncnc1Nc1ccc(Cl)cc1
Reactant: CCOC(CC)(OCC)OCC
Agent: CCS(=O)(=O)O
Product: CCc1nc2c(Cl)ncnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
6-chloro-N4-(4-chlorophenyl)pyrimidine-4,5-diamine obtained in step 1 (1.5 g, 5.88 mmol) was dissolved in triethyl ortho propionate (11.8 ml, 58.8 mmol) at room temperature. Ethanesulfonic acid (0.48 mL, 5.88 mmol) was added slowly to the resulting solution at 0 r and warmed to room temperature. The reaction mixture thus obtained was stirred for 6 hours at 50° C. The resulting mixture was filtered with NaHCO3(aq)/H2O. The collected solid was dried under reduced pressure to obtain the title compound (1.39 g, 81%) as white solid.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4-fluoro-2-methoxyphenylboronic acid (CAS 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=233.108 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[S:15][CH:16]=1)=O)C.O.[OH-].[Na+]>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:10][OH:9])[N:13]=2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1csc(-c2ccc(OC)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nc(CO)cs2)cc1
Temperature: 60 °C
Yield: 64.6 %

Procedure:
To an ice-cold suspension of LAH (0.08 g, 2.07 mmol) in 10 ml of anhydrous THF was added a solution of 2-(4-Methoxy-phenyl)-thiazole-4-carboxylic acid ethyl ester (0.26 g, 0.98 mmol) in 5 ml of THF. The reaction mixture was heated up to 60° C. for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was cooled to 0° C., water (2.0 ml) was added followed by the addition of 15% NaOH solution (2 mL) and finally 4 ml of water. The resulting solution was filtered through celite bed and concentrated under reduced pressure; water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated to give the desired product (0.14 g, 64%).