Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](=[O:32])[CH2:30]Br)=[CH:28][C:23]=2[O:22][CH2:21]1>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:30]=1[C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH2:21][O:22][C:23]=2[CH:28]=1)=[O:32]
Reactant: CN1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: N#CN
Reactant: O=C(CBr)c1ccc2c(c1)OCO2
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4ccc5c(c4)OCO5)s3)cc2)CC1
Yield: 75 %

Procedure:
This compound was prepared in 75% yield from cyanamide (Aldrich), 1-(4-isothiocyanatophenyl)-4-methylpiperazine (of Example 1), and 1-(1,3-benzodioxol-5-yl)-2-bromoethanone (of Example 11) following the procedure used to in Example 24.
Reaction SMILES: C(NC(C1C=CC2SC3C(=CC=CC=3)N([CH:21]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:22][CH3:23])C=2C=1)=O)CC.[CH:29]1(CBr)[CH2:31][CH2:30]1.[C:34](=O)([O-])[O-].[Na+].[Na+].[I-:40].[Na+]>CC(C)=O.CN(C)C=O>[I-:40].[CH:22]1([CH2:21][N+:24]2([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:23][CH2:34]1
Reactant: CCCNC(=O)c1ccc2c(c1)N(C(CC)N1CCCC1)c1ccccc1S2
Reactant: BrCC1CC1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CC(C)[N+]1(CC2CC2)CCCC1
Reaction time: 40 h

Procedure:
A suspension of N-propyl-10-[1-(1-pyrrolidinyl)-propyl]-2-phenothiazinecarboxamide, L series (0.6 g), cyclopropylmethyl bromide (0.74 cc), sodium carbonate (1 g) and sodium iodide (0.5 g) in a mixture of acetone (25 cc) and dimethylformamide (0.5 cc) is brought to reflux with stirring for 40 hours, cooled and filtered, and the filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 55°-60° C. The orange-colored oily residue (1.98 g) is taken up with stirring with isopropyl ether (35 cc) for 16 hours at a temperature in the region of 20° C. The suspension obtained is filtered and the solid is drained, washed with isopropyl ether (2×10 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 37° C. This yellow solid (1.25 g) is taken in dichloromethane (12 cc) with stirring for 2 hours and the suspension obtained is filtered. The filtrate is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and the orange-colored oily residue (0.69 g) is solidified by stirring for one hour in diethyl ether (30 cc). The solid formed is separated by filtration, washed with diethyl ether (2×5 cc), drained and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 37° C. 1-Cyclopropylmethyl-1-[2-propyl]pyrrolidinium iodide, L series (0.59 g), is thereby obtained in the form of an orange-yellow solid, m.p. about 125°-130° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].[C:25]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[C:13]([O:14][CH3:25])=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=[CH2:3]
Reactant: O=C([O-])[O-]
Reactant: C=CCc1c(O)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccc(Cl)cc3)c12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of 5-allyl-4-(4-chloro-phenylamino)-7-methoxy-quinazolin-6-ol (0.45 g, 1.32 mmol) (from Example 16, Step D, supra) in acetone (30 mL) was added K2CO3 (0.36 g, 2.6 mmol) and methyl iodide (0.75 g, 5.3 mmol) (Aldrich). The reaction mixture was heated with stirring at 90° C. for 4 hours. The mixture was cooled to room temperature, filtered and the filtrate was concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.01) as eluent to give the desired (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-(4-chloro-phenyl)-amine as a white solid. (Yield 0.3 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[C:18]([NH:19][CH2:20][CH2:21][NH:22][C:23](=O)[C:24]2[CH:29]=CC([N+]([O-])=O)=CC=2)=[CH:17][C:16](=[O:34])[N:15]([CH3:35])[C:14]1=[O:36].[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:38]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][N:13]1[C:18]([N:19]2[CH2:20][CH2:21][N:22]([CH2:23][CH2:24][CH2:29][O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[NH2:1])[CH2:38][CH2:37]2)=[CH:17][C:16](=[O:34])[N:15]([CH3:35])[C:14]1=[O:36]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: Cn1c(NCCNC(=O)c2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3N)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
1.54 g of 2-amino-4-nitrophenol, 2.82 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound 139) and 2.88 g of triphenylphosphine were suspended in 20 ml of anhydrous tetrahydrofuran, followed by the addition of 1.92 g of diethyl azodicarboxylate. The thus-prepared mixture was stirred for 1 hour at room temperature and a precipitate was collected by filtration. The precipitate was washed with chloroform-ether to obtain 1.44 g of crytals. The crystals were recrystallized from ethanol-chloroform, thereby obtaining 0.6 g of 1,3-dimethyl-6-{4-[3-(2-amino-4-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:5])C.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[C:11]1([C:9]2[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][CH:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)cs1
Yield: 54 %

Procedure:
4-Phenyl-thiazole-2-carboxylic acid ethyl ester, commercially available from Pharma Core, (1.0 g, 4.28 mmol) in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 10 mL) was treated with lithium hydroxide monohydride (514 mg, 12.8 mmol) at room temperature for three hours. After the reaction was complete, solvent was evaporated. To the residue, water was added, and pH of the resulting solution was adjusted to ˜1-2 by addition of dilute hydrochloride acid (1N). The white precipitation was collected by centrifugation and further washed with water to give 4-phenyl-thiazole-2-carboxylic acid (473 mg, 54%). LCMS calcd for C10H7NO2S (m/e) 205, obsd 206 (M+H).
Reaction SMILES: [CH3:1][Si:2]([Cl:5])([CH3:4])[CH3:3].[OH2:6]>>[CH3:1][Si:2]([O:6][Si:2]([CH3:4])([CH3:3])[CH3:1])([CH3:4])[CH3:3].[ClH:5]
Reactant: O
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)O[Si](C)(C)C
Product: Cl

Procedure:
TMCS reacts with the water in the hydrogel to form HMDSO and HCl. Following separation, HMDSO and HCl can be reacted again under suitable conditions to form TMCS and water.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][OH:25]>>[OH:25][CH2:24][C@H:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: N[C@@H](CO)c1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N[C@@H](CO)c3ccccc3)cc2c1=O
Yield: 75 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-2-phenyl-ethanol according to the GPA affording 31.2 mg (75%) of a red powder. Rt=4.11 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[C:22]1([N:28]=[C:29]=S)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:19][C:29]([NH:28][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:21][N:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: S=C=Nc1ccccc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4ccccc4)o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) in DMF (3 mL) add phenyl isothiocyanate (97 uL, 0.512 mmol) and stir for 3.5 hr. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 1 hr. Upon cooling to room temp dilute the reaction with EtOAc (75 mL) and extract with water (15 mL). Evaporate the organic phase and suspend the resulting residue in 1 N NaOH (5 mL). Collect the solid and wash with water. Take the solid up in boiling toluene/EtOAc. Allow to cool. Collect the solid, wash with Et2O, and dry in a vac-oven to afford the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-d6) ppm 7.03 (t, J=7.39 Hz, 1 H) 7.39 (t, J=7.96 Hz, 2 H) 7.63-7.69 (m, 3 H) 7.71 (d, J=1.26 Hz, 1 H) 7.73 (t, J=1.89 Hz, 1 H) 7.77 (tautomer A, d, J=8.59 Hz, 1 H) 7.83 (tautomer B, dd, J=8.46, 1.52 Hz, 1 H) 7.91 (dd, J=8.46, 1.52 Hz, 1 H) 8.05 (tautomer B, d, J=1.01 Hz, 1 H) 8.17 (tautomer A, s, 1 H) 10.68 (s, 1 H) 13.30 (d, J=4.17 Hz, 1 H); MS (m/z)=422.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]([CH2:35][OH:36])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[OH:36][CH2:35][C@H:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=1)=[O:22])[CH3:34]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (400 mg, 0.87 mmol), D-alaninol (131 mg, 1.75 mmol), HBTU (431 mg, 1.14 mmol), HOBt (153 mg, 1.14 mmol) and DIPEA (0.31 ml, 1.75 mmol) were combined with DMF (6 ml) to give a light yellow solution. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH) to provide 250 mg (56%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide as an off-white solid. MS: (M+H)+=516.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH2:9][N:8]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:7]1)=[O:5])C.C1NCC2C1CC1C(C#N)=CSC=12>Cl>[C:18]1([CH:16]([N:8]2[CH2:9][CH:10]([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C1CN(C(C)c2ccccc2)CC1c1ccsc1
Agent: Cl
Agent: N#Cc1csc2c1CC1CNCC21
Product: CC(c1ccccc1)N1CC(C(=O)O)C(c2ccsc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
The product from step b), diastereomer 1 (1.4 g, 4.3 mmol) was dissolved in 12 M HCl (10 mL) and was stirred at 80° C. for 12 hours. The reaction mix then was cooled to room temperature and evaporated to dryness to afford the subtitle compound. MS calculated for C17H19NO2S +H: 302, observed: 302.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:24]([CH3:25])[CH:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=3)=[C:18]3[C:13]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:15](=[O:31])[N:16]([CH3:30])[C:17]3=[O:29])=[N:12]2)=[CH:2]1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C(P(=O)(OCC)OCC)#N>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:24]([CH3:25])[CH:23]=[C:22]([C:26]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])=[O:28])[CH:21]=3)=[C:18]3[C:13]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:15](=[O:31])[N:16]([CH3:30])[C:17]3=[O:29])=[N:12]2)=[CH:2]1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3csc4ccccc34)nc21
Reactant: CN(C)CCN
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN(C)C)cn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-[2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 562.18 (M+H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]([CH3:33])[N:31]=[CH:30][C:29]=2[CH:34]=[O:35])=[CH:24][CH:23]=1>O1CCCC1>[Cl:13][C:14]1[C:19]([CH:34]([C:29]2[CH:30]=[N:31][N:32]([CH3:33])[C:28]=2[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[OH:35])=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(-c2c(C=O)cnn2C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 240 mL, 0.60 mol) was added drop-wise to a solution of diisopropylamine (85.2 mL, 0.60 mol) in tetrahydrofuran (600 mL) at −78° C. After the reaction had stirred for 30 minutes at −78° C., a solution of 4,6-dichloropyrimidine (89.4 g, 0.600 mol) in tetrahydrofuran (600 mL) was added drop-wise at about −90° C., and stirring was continued for 1 hour. To this mixture was added drop-wise a solution of 5-(4-methylphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (C3) (60.0 g, 300 mmol) in tetrahydrofuran (600 mL) at about −90° C. After completion of the addition, the reaction mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with acetic acid (60 g); the mixture was warmed to room temperature, and then concentrated under reduced pressure to remove tetrahydrofuran. The residue was dissolved in ethyl acetate (2 L) and washed with saturated aqueous sodium bicarbonate solution (1 L). The organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate yielded the product as a white solid. Yield: 82.0 g, 235 mmol, 78%. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 3.72 (s, 3H), 6.26 (s, 1H), 7.17 (br AB quartet, JAB=8 Hz, ΔνAB=32 Hz, 4H), 7.66 (s, 1H), 8.55 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([C:21](=[O:22])[CH2:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[O:12][CH3:13]
Reactant: COc1ccccc1F
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Cc2ccccc2)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of aluminum chloride (9.4 g, 70.5 mmol) in a solution of 2-fluoroanisole (6.6 mL, 58.8 mmol) and anhydrous chloroform (200 mL) was cooled to 0° C. under a blanket of dry nitrogen. A solution of phenylacetyl chloride (8.6 mL, 64.7 mmol) in anhydrous chloroform (50 mL) was added to the vigorously stirred suspension over 20 minutes keeping the reaction temperature <5° C. The yellowish solution was stirred at 0° C. for 1 hour, poured into ice (200 mL) and stirred without temperature control for 16 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic solution was dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from boiling hexane to yield, upon filtration and drying, 1-(3-fluoro-4 methoxyphenyl)-2-phenyl-ethan-1-one (12.9 g, 90%) as white crystals: 1H NMR (CDCl3 /300 MHz) δ 7.82-7.72 (m, 2H), 7.35-7.24 (m, 5H), 6.98 (dd, J=8.46, 8.26 Hz, 1H), 4.22 (s, 2H), 3.94 (s, 3H). 19F NMR (CDCl3 /282.2 MHz) -134.875 (m).
Reaction SMILES: Cl[C:2]1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=[CH:4][N:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34](C(C)C)(=[O:36])=[O:35])[C:24]([Cl:40])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:61][O:62][C:63]1[CH:64]=[CH:65][C:66]2[CH2:72][CH2:71][CH:70]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)[CH2:69][CH2:68][C:67]=2[C:79]=1[NH2:80]>>[Cl:40][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([N:3]([CH3:4])[CH3:2])(=[O:35])=[O:36])=[N:26][C:21]([NH:80][C:79]2[C:67]3[CH2:68][CH2:69][CH:70]([N:73]4[CH2:74][CH2:75][O:76][CH2:77][CH2:78]4)[CH2:71][CH2:72][C:66]=3[CH:65]=[CH:64][C:63]=2[O:62][CH3:61])=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Product: COc1ccc2c(c1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)CCC(N1CCOCC1)CC2

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford 2-[5-Chloro-2-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino)-pyrimidin-4-ylamino]-N,N-dimethyl-benzenesulfonamide. LC/MS (ESI): 587.18. 1H NMR (400 MHz, DMSO, d6) δ 9.48 (s, 2H), 8.67 (m, 1H), 8.20 (m, 1H), 7.70 (m, 1H), 7.15 (m, 2H), 6.89 (m, 1H), 3.72 (s, 3H), 3.65 (m, 4H), 3.12 (m, 5H), 2.88 (m, 2H), 2.72 (m, 2H), 2.67 (s, 6H), 2.32 (m, 2H), 1.44 (m, 2H).
Reaction SMILES: C(O)(=O)C.C([N:12]1[CH2:24][CH2:23][C:15]2([CH2:20][C:19](=[O:21])[NH:18][C:17](=[O:22])[CH2:16]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:20]1[C:15]2([CH2:14][CH2:13][NH:12][CH2:24][CH2:23]2)[CH2:16][C:17](=[O:22])[NH:18][C:19]1=[O:21]
Reactant: O=C1CC2(CCN(Cc3ccccc3)CC2)CC(=O)N1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1CC2(CCNCC2)CC(=O)N1
Reaction time: 18 h
Yield: 86.2 %

Procedure:
Palladium hydroxide (20% on carbon; 100 mg) and acetic acid (250 μL) were added to a solution of 9-benzyl-3,9-diazaspiro[5.5]undecane-2,4-dione (0.38 g, 1.40 mmol) in ethanol (5 mL). The reaction vessel was evacuated and back-filled with nitrogen (3×), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the acetate salt of the title compound (220 mg). MS 183.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: O=C(CCl)N1CCOCC1
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c2c(OCC(=O)N3CCOCC3)nsc2n1
Temperature: 40 °C
Yield: 9.3 %

Procedure:
Pyridinothiazolone 4 (200 mg, 1.22 mmol), was treated with 2-chloro-1-morpholinoethanone (225 mg, 1.25 mmol) and Et3N (370 mg, 3.66 mmol) in anhydrous CH2Cl2 (25 mL) at reflux (40° C.) for 24 h, and then washed with 1 M HCl(aq). The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of EtOAc/hexane (1:1) to give the title compound (35 mg, 9% yield) in addition to the main N-alkylation product 19 (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]([CH3:23])[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:17])[C:12]([C:24]#[N:25])=[CH:11][C:10]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1.N>C1COCC1.CO>[NH2:25][C:24]1[C:12]2[C:13](=[N:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:11]=2)[N:15]([CH3:23])[C:16](=[O:17])[C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CC(=O)N(C)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To the product of Step A EXAMPLE 91 (100 mg) in THF (1 mL) was added 2 mL of NH3 in methanol (7 M). The reaction stirred for 3.5 hours at room temperature before it was concentrated. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3. The solution was dried (Na2SO4) and concentrated to afford the title compound. HPLC/MS: 488.0 (M+1), 490.0 (M+3); Rt=4.05 min.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@@H:22]([C:24](=[O:38])[N:25]([CH:35]4[CH2:37][CH2:36]4)[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=4[Cl:34])[CH2:21][C@@H:20]([NH2:39])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.Cl[C:42]([O:44][CH2:45][CH2:46][O:47][CH3:48])=[O:43]>CC#N>[CH3:48][O:47][CH2:46][CH2:45][O:44][C:42](=[O:43])[NH:39][C@@H:20]1[CH2:21][C@H:22]([C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:23][NH:18][CH2:19]1
Reactant: N[C@@H]1C[C@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: COCCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Product: COCCOC(=O)N[C@H]1CNC[C@@H](C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)C1

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-[cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-piperidine-1 carboxylic acid 9H-fluoren-9-ylmethyl ester; hydrochloride and 2-methoxyethyl chloroformate. MS (LC-MS): 444.2/446.1 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 4.74 min.