Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]([CH3:12])[S:8]([CH3:11])(=[O:10])=[O:9].[C:13]1(=[N:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH3:6][N:7]([CH3:12])[S:8]([CH2:11][C:13]1([NH:19][S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:10])=[O:9]
Reactant: CN(C)S(C)(=O)=O
Reactant: CC(C)(C)S(=O)N=C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CC1(NS(=O)C(C)(C)C)CCCCC1
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
n-Butyllithium (1.3 eq, 8.07 mL of a 1.6M soln in hexanes) was added dropwise to a cooled (−78° C.) solution of N,N-dimethyl methanesulfonamide (1.35 eq, 1.65 g) in 100 mL of dry THF under anhydrous atmosphere. The mixture was stirred for 30 min at that temperature and then transferred via cannula to a solution of sulfinyl imine 1200-B (2.0 g) in 100 mL of dry THF at −78° C. After addition was completed, the reaction mixture was stirred for 1 h. The reaction was quenched at −78° C. by addition of 20 mL of aqueous saturated ammonium chloride solution. The mixture was allowed to reach room temp and then partitioned between dichloromethane (300 mL) and aqueous saturated sodium bicarbonate solution (300 mL). The aqueous layer was back extracted with dichloromethane (2×200 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel (gradient:dichloromethane/hexanes; 1:1 to 30% acetone in dichloromethane/hexanes; 1:1) to afford the product 1200-C (1.36 g; 42%) as a colorless oil.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[S:15])[NH:13][NH2:14])=[CH:7][CH:6]=1)([OH:4])(=[O:3])=[O:2].[Na].[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[CH:28]=O>>[OH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]=1[CH:28]=[N:14][NH:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([S:1]([OH:4])(=[O:2])=[O:3])=[CH:10][CH:9]=1)=[S:15]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: NNC(=S)Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Product: O=S(=O)(O)c1ccc(NC(=S)NN=Cc2c(O)ccc3ccccc23)cc1
Yield: 23 %

Procedure:
The procedure described in example 4 was followed here, using 4-(4-sulfophenyl)-3-thiosemicarbazide, sodium salt in place of 4-(naphth-1-yl)thiosemicarbazide and 2-hydroxy-1-naphthaldehyde in place of 2,4,6-trihydroxybenzaldehyde to give the title compound (23%) as a solid. MS (ES−) m/e 400 [M−H]−.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[I:19]I>CN(C)C=O>[I:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: II
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(I)c2[C@@H]2CCCN12

Procedure:
44.26 g (185 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was stirred at 100° for 4 hours with 162.8 g (645 mmol) of iodine in 300 ml of N,N-dimethylformamide. The reaction mixture was evaporated, the residue was taken up in water and methylene chloride, decolorized with sodium thiosulphate and neutralized with sodium bicarbonate. The aqueous phase was separated and extracted four times with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. By chromatography of the crude product on silica gel while eluting with ethyl acetate and subsequent recrystallization from methylene chloride and methanol there was obtained (S)-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 222°-223°.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH:8]1[C:17]2[C:12](=[CH:13][C:14]([N:18]3[CH2:34][CH2:33][C:21]4([CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH2:25]1[C:21]2([CH2:20][CH2:19][N:18]([C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[CH:8]=[N:9][CH:10]=[CH:11]4)[CH2:34][CH2:33]2)[CH2:22][CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc4cnccc4c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2cc(N3CCC4(CCNC4)CC3)ccc2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (2 ml) was added to a cooled (0° C.) solution of tert-butyl 8-(isoquinolin-6-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.544 mmol, 1.0 eq.) in methylene chloride (10 ml) and the reaction mixture was stirred at room temperature for 1 h. When the reaction was complete, the solvent was removed on a rotary evaporator. The crude product was employed directly in the next step.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:34]2[N:33]=[CH:32][N:31]=[C:23]([NH:24][C@H:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[OH:30])[C:22]=2[N:21]=[CH:20]1)(=O)C.C(N)(C)(C)C>CO>[OH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][C@@H:25]1[NH:24][C:23]1[C:22]2[N:21]=[CH:20][N:19]([C:34]=2[N:33]=[CH:32][N:31]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCC[C@@H]4O)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Solvent: CC(C)(C)N
Product: OC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCC[C@@H]4O)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of 2',3',5'-tri-O-acetyl-N-[(1S,trans)-2-hydroxycyclopentyl]adenosine (0.34 g) in methanol (7 ml) containing t-butylamine (3 ml) was allowed to stand at 23° for 16 h. The solution was evaporated to dryness and residual t-butylamine was removed azeotropically with methanol to leave a glass. Crystallisation of a sample of this glass (0.19 g) from a mixture of methanol and ethyl acetate (1:20) gave the title compound (0.15 g), m.p. 160°-163°. Its chromatographic behaviour resembled that of authentic material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Br:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[CH2:14]1[O:16][CH2:15]1.Cl.O>CCOCC>[F:1][CH:2]1[C:7]([O:8][C:9]([F:10])([F:11])[F:12])([O:16][CH2:15][CH3:14])[CH:6]=[CH:5][C:4]([Br:13])=[CH:3]1
Reactant: Fc1cc(Br)ccc1OC(F)(F)F
Reactant: C1CO1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CCOC1(OC(F)(F)F)C=CC(Br)=CC1F
Temperature: -50 °C
Yield: 30.8 %

Procedure:
A Grignard reagent prepared from 3-fluoro-4-trifluoromethoxyphenylbromide (200.0 g, 772 mmol) and dried Mg (18.8 g, 774 mmol) in ether was cooled down to -50° C. in a nitrogen atmosphere, followed by dropwise adding thereto a 100 ml ether solution of ethylene oxide (100 g, 2.27 mol), stirring the reaction solution at 0° C. for 2 hours, adding the resulting reaction product to 6N HCl, extracting the product with toluene, washing the extraction solution successively a saturated aqueous solution of sodium bicarbonate and water, drying over the organic layer over magnesium sulfate, distilling off the solvent, adding to the residue, 47% hydrogen bromic acid (300 ml) and xylene (300 ml), refluxing the mixture for 9 hours, while removing water formed by the reaction by means of Dean-Stark, adding water (500 ml) to the resulting reaction product, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, distilling off the solvent, and distilling the residue under reduced pressure, to obtain 3-fluoro-4-trifluoromethoxyphenetylbromide (68.3 g, 238 mmol). Yield: 30.7%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]1([N:28]2[CH2:37][C:36]([CH3:39])([CH3:38])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:40]=O)[CH:34]=3)[CH2:29]2)[CH2:27][CH2:26]1.C(OCC)(=O)C>ClCCl.CCCCCC>[Br:21][C:20]([Br:24])=[CH:40][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([CH:25]1[CH2:26][CH2:27]1)[CH2:37][C:36]2([CH3:39])[CH3:38]
Reactant: CC1(C)CN(C2CC2)Cc2ccc(C=O)cc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC1(C)CN(C2CC2)Cc2ccc(C=C(Br)Br)cc21
Reaction time: 0.5 h

Procedure:
A stirred, cooled (ice-bath) solution of triphenyl phosphine (0.53 g, 2 mmol) in anhydrous dichloromethane was treated with carbon tetrabromide (0.35 g, 1 mmol) under argon. After 0.5 h, a solution of 2-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline-6-carboxaldehyde (Intermediate 25, 0.13 g, 0.57 mmol) in dichloromethane (2 mL) was cannulated into the reaction mixture. After 1.5 h between 0° C. and 10° C., the reaction mixture was subjected to flash column chromatography over silica gel (230-400 mesh) using 3-5% ethyl acetate in hexane as the eluent to afford the title compound as a viscous, pale yellow oil (0.18 g, 82%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.Br[CH2:18][C:19]([C:21]1[C:22]([CH3:31])=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[O:25][CH2:24]2)=[O:20].CCN(C(C)C)C(C)C>O1CCCC1.[Cl-].[Na+].O>[OH:1][CH2:2][CH2:3][CH:4]1[N:9]([CH2:18][C:19]([C:21]2[C:22]([CH3:31])=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[O:25][CH2:24]3)=[O:20])[CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: Cc1c(C(=O)CBr)ccc2c1COC2=O
Reactant: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2CCO)ccc2c1COC2=O

Procedure:
tert-Butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (6.91 g, 30.0 mmol) and 5-(2-bromoacetyl)-4-methylisobenzofuran-1(3H)-one (6.73 g, 25 mmol) were dissolved in tetrahydrofuran (100 mL) then added Hunig's base (8.73 mL, 50.0 mmol) and stirred at RT overnight. The reaction was poured into brine and extracted with EtOAc (2×). The combined organic layer was dried over Na2SO4, filtered and evaporated to dryness. The crude product was chromatographed through an ISCO Redi-Sep 330 g column and eluted with 5% MeOH/DCM solvent system to the title compound. LC-MS (IE, m/z): 419 [M+1]+.
Reaction SMILES: C(O[C:9]([N:11](C)[C@H:12]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])=O)C1C=CC=CC=1>C(O)C.[Pd]>[Si:32]([O:31][CH2:30][C@@H:12]([NH:11][CH3:9])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CN(C(=O)OCc1ccccc1)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
(S)-tert-butyl 4-(4-((benzyloxycarbonyl)(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentanoyl)piperazine-1-carboxylate (21.5 g) and 10% Pd/C (2.2 g) in ethanol (100 mL) was charged with H2 (50 psi). The resulting mixture was stirred at RT overnight and filtered. The filtrate was concentrated to give (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentanoyl)piperazine-1-carboxylate (16 g, crude), which was sued without further purification. LRMS (M+H) m/z 430.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][NH:33][CH2:32]3)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][CH2:34][NH:33][CH2:32]3)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc5c(c4)CNC=N5)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Nc1nc(O[C@H](c2ccc3c(c2)CNCN3)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(3,4-dihydroquinazolin-6-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (a by-product from the N-CBZ deprotection of Example 55bk) using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[CH3:13].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH2:22].N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[NH:22][C:7](=[O:8])[C:6]1[CH:10]=[C:11]([CH3:12])[C:3]([O:2][CH3:1])=[C:4]([CH3:13])[CH:5]=1
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: Nc1cnc(Cl)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C)cc(C(=O)Nc2cnc(Cl)cc2Cl)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
With ice cooling, 1.20 g of 4-methoxy-3,5-dimethylbenzoyl chloride, dissolved in 1 ml of dry dichloromethane were initially added dropwise to a solution of 0.82 g of 4,6-dichloropyridin-3-ylamine in 8 ml of dry dichloromethane. A solution of 0.4 ml of absolute pyridine in 1 ml of dry dichloromethane was then added, and the reaction was stirred at 0° C. for 2 h, the product partially precipitating slowly. Approx. 10 ml of 10% strength aqueous sodium bisulfate solution were then added, and the mixture was stirred for five minutes. The aqueous phase was then decanted off and the solid-containing organic phase was concentrated under reduced pressure and freeze-dried. This gave 1.63 g (100%) of the product, which was used for the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:15][CH2:16]O>>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1])[CH3:16]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (0.85 g, 4.22 mmol) in anhydrous EtOH (50 mL) was bubbled with dry hydrogen chloride for 2 h at room temperature and the mixture was then stirred at room temperate overnight. After evaporation of solvent, water (100 mL) was added and the precipitates were collected by filtration and dried to give 2-chloro-3-nitro-benzoic acid ethyl ester.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=O)(=[O:3])[CH3:2].C1C=[C:23]2[N:25]=N[N:27](O)[C:22]2=CC=1.O.Cl.NCC#N.CN1CCOCC1>C(OCC)(=O)C.C(Cl)Cl.C(Cl)CCl>[CH2:12]([S:11][CH2:10][CH:6]([C:7](=[O:9])[NH:27][CH2:22][C:23]#[N:25])[CH2:5][S:4][C:1](=[O:3])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: CC(=O)SCC(CSCc1ccccc1)C(=O)O
Agent: Cl
Agent: N#CCN
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)SCC(CSCc1ccccc1)C(=O)NCC#N
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 96.1 %

Procedure:
A mixture of 3-acetylsulfanyl-2-benzylsulfanylmethyl-propionic acid (0.200 g), prepared as in Reference 10, HOBt hydrate (0.13 g), aminoacetonitrile hydrochloride (0.15 g) and EDC (0.26 g) was treated with methylene chloride (6 mL) and N-methylmorpholine (0.35 mL). After stirring for 80 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed sequentially with water, aqueous sodium bicarbonate and saturated aqueous sodium chloride. The solution was dried over magnesium sulfate and evaporated to give thioacetic acid S-[3-benzylsulfanyl-2-(cyanomethyl-carbamoyl)-propyl] ester (0.218 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:24][N:23]=[C:22]([CH3:25])[CH:21]=1)=[CH:16][CH:15]=3.I[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:28](=[O:29])[N:27]([CH3:30])[C:12]2[N:13]([CH3:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:21]=[C:22]([CH3:25])[N:23]([CH3:32])[N:24]=1)=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)[nH]n1
Product: Cc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, using 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(3-methyl-1H-pyrazol-5-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one described in Example 46 above and iodomethane.
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:24](B1C2CCCC1CCC2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[ClH:1].[CH2:24]([C:14]1[CH:15]=[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncc(Cc3ccccc3)cc2OCc2ccccc2)n1
Yield: 92 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1) (0.125 g, 0.332 mmol), 9-benzyl-9-bora-bicyclo[3.3.1]nonane (1.99 mL, 0.997 mmol), PdCl2(dppf) dichloromethane adduct (0.0273 g, 0.0332 mmol), were placed in DMF (6 mL), and water (0.6 mL) and heated to 60° C. for 18 hours. The reaction mixture was cooled and partitioned between water and DCM. The layers were separated and the organic layer was dried, filtered, and concentrated. Crude material was purified by silica gel to give the free base of the title compound (92%). The free base was purified by reverse phase chromatography. The purified free base was dissolved in DCM and 2M HCl was added. The mixture was concentrated to give 5-benzyl-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.038 g, 29.5% yield). 1H NMR (DMSO-d6) δ 7.88 (s, 1H), 7.57 (m, 3H), 7.38 (m, 3H), 7.27 (m, 4H), 7.21 (m, 1H), 6.83 (s, 1H), 5.29 (s, 2H), 3.94 (s, 2H), 2.31 (s, 3H). Mass spectrum (apci) m/z=388.1 (M+H-HCl).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:36][CH:35](F)[CH2:34]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[N:19]=2)[CH2:11][CH2:10]1)[CH3:2].F[C:40]1C=CC(C2N=C(C3CCNCC3)N(CCN3CC(C)C3)C=2)=CC=1C(F)(F)F>>[CH2:1]([C:3]1[C:4]([NH2:38])=[N:5][CH:6]=[N:7][C:8]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]2[N:16]([CH2:31][CH2:32][N:33]3[CH2:34][CH:35]([CH3:40])[CH2:36]3)[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([C:27]([F:28])([F:29])[F:30])[CH:21]=3)[N:19]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: CC1CN(CCn2cc(-c3ccc(F)c(C(F)(F)F)c3)nc2C2CCNCC2)C1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(F)C2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCN2CC(C)C2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-ethyl-6-(4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-fluoroazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-4-amine using 4-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(3-methylazetidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine instead of 4-[1-[2-(3-Fluoro-azetidin-1-yl)-ethyl]-4-(4-fluoro-3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine. LC-MS: (M+1=532, obsd.=532).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:6]=2[N:7]=1
Reactant: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
503 mg 2,4-dichloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (5) (2.5 mmol) and 523 mg TsCl (2.75 mmol) were dissolved in 20 mL of DMF. After cooling to 0° C., 200 mg NaH (2.75 mmol) was slowly added under N2. The reaction mixture was stirred at 0° C. for 30 minutes and quenched by adding 10 mL of 10% aqueous NH4Cl at this temperature, then extracted with EtOAc (3×50 mL). Combined organic layers were washed with brine, dried over Na2SO4 and purified by flash column chromatography to give the title compound as light yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=2)[C:11](=[O:20])[N:10]2[CH2:21][CH2:22][N:23]=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[C:11](=[O:20])[N:10]2[CH2:21][CH2:22][N:23]=[C:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)C(=O)N1CCN=C1N2Cc1ccccc1
Agent: Br
Product: O=C1c2cc(O)ccc2N(Cc2ccccc2)C2=NCCN12
Reaction time: 2 h

Procedure:
One gram of 10-benzyl-7-methoxy-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one is added slowing to 10 ml. of 48% hydrobromic acid and the resulting mixture refluxed with stirring for 2 hours. The resulting mixture is cooled and the precipitated material filtered off and dissolved in 1N. sodium hydroxide. The resulting solution is washed twice with methylene chloride and slowly acidified to about pH6 with 2N hydrochloric acid to form a crystalline material which is filtered off, washed with water, dried by suction and dissolved in chloroform and a minor amount of methanol, treated with charcoal and concentrated on a steam bath to crystallize 10-benzyl-7-hydroxy-2,3-dihydro-imidazo[2,1-b]quinazolin-5(10H)-one, m.p. 225°-227°C.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:25])/[CH:14]([CH2:21][CH2:22][CH2:23]Br)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:9]([O:26][CH3:27])[C:8]([CH3:28])=[C:7]2[C:3]=1[C:4](=[O:29])[O:5][CH2:6]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH4+].[Cl-]>C1COCC1>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](/[CH:14]2[CH2:21][CH2:22][CH2:23][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])\[CH3:25])=[C:9]([O:26][CH3:27])[C:8]([CH3:28])=[C:7]2[C:3]=1[C:4](=[O:29])[O:5][CH2:6]2
Reactant: CCOC(=O)CC(CCCBr)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC1/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.6 %

Procedure:
A solution of ethyl (E) 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-(3-bromopropyl)-4-methylhex-4-enoate (420 mg) was cooled to -78° C. in THF (50 ml), and a 1M solution of sodium bis (trimethylsilyl) amide (1.88 ml) in THF was added slowly. The reaction was stirred for 45 min at -78° C., and then allowed to warm to 0° C. over 15 minutes, at which time 5 ml of 1N NH4Cl) was added. The THF was evaporated, the aqueous layer extracted with ether, the ether layer washed with 1N HCl, brine, and then dried. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (20%-25% ethyl acetate in hexanes) to give ethyl (E) 2-[-3-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-methylpropenyl]-cyclopentanecarboxylate (235 mg), a compound of Formula I-ZH-A1, as an oil.