Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([N:11]([CH3:32])[C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[N:7]=[CH:8][C:9]=2[N:10]=1)(=[O:35])[CH3:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(N)sc2n1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(N(C)c3cccc(NC(=O)c4cccc(C(C)(C)C#N)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (152 mg, 343 μmol) produced in Example D5(i) in pyridine (4 mL) was added acetyl chloride (74 μL, 1.03 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (102 mg, 61%) as a pale-purple solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29](O)=[O:30])=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:19][CH:18]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:29]([C:24]1[C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:27][N:26]([CH3:28])[N:25]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Yield: 95.2 %

Procedure:
The title compound (3.96 g) was prepared from (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl carboxylic acid (2.20 g) according to the method of D40.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)Cl>[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21][C:24]([NH:23][CH3:22])=[O:25])(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)NS(=O)(=O)c1ccccc1OCCCl
Temperature: 25 °C

Procedure:
5.9 g of triethylamine is added dropwise to a suspension of 11.0 g of 2-(2-chloroethoxy)-phenylsulfonamide, 50 ml of methylene chloride and 3.3 g of methyl isocyanate within 10 minutes at a temperature of 20°-25° C. The resulting clear solution is stirred for a further hour at room temperature and evaporated to dryness. The residue is solved in 5% aqueous sodium carbonate. After acidification of this solution with 10% hydrochloric acid 12.5 g of N-[2-(2-chloroethoxy)-phenylsulfonyl]-N'-methylurea precipitate therefrom, m.p. 218°-222° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>ClCCl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]2[C:43]3[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=3[C:37]([C:47]3[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=3)=[N:36]2)[CH2:13][CH2:12]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Nc3nc4ccccc4s3)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A solution of 220 mg (0.66 mmol) of 4-(benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in MeOH and stirred over 100 mg of sodium bicarbonate for 1 h. The solid was filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 220 mg (0.60 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 240 mg (66%) of a white solid. MS (electrospray): exact mass calculated for C30H33F3N6O2S: 598.23; m/z found, 599.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.78 (d, J=8.22 Hz, 1H), 7.72 and 7.68 (A and B of AB quartet, J=8.41 Hz, 2H), 7.64 (d, J=8.22 Hz, 1H), 7.56 (bd, J=8.02 Hz, 1H), 7.51 (bd, J=8.02 Hz, 1H), 7.29 (bd, J=7.63 Hz, 1H), 7.08 (bt, J=7.63 Hz, 1H), 5.29 (br s, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.23-4.16 (m, 1H), 4.16-4.08 (m, 1H), 4.06-3.98 (m, 2H), 3.92-3.65 (m, 3H), 3.03-2.70 (m, 4H), 2.52-2.41 (m, 3H), 2.26-2.18 (m, 1H), 2.21 (s, 1.5H), 2.16 (s, 1.5H), 2.16-2.08 (m, 2H), 1.66-1.44 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[N+:20]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>CN(C)C=O.O.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>[NH2:1][C:2]1[C:3]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:4][C:5]([Br:9])=[CH:6][C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:28]=1
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
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: O
Solvent: CN(C)C=O
Product: Nc1c(-c2cccc([N+](=O)[O-])c2)cc(Br)cc1S(=O)(=O)O
Temperature: 70 °C
Yield: 80.4 %

Procedure:
To a solution of 1.9 g (5 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 1.6 g (15 mmol) of sodium carbonate in 25 ml of dimethylformamide and 12.5 ml of water are added successively, under a nitrogen atmosphere, 0.231 g (0.2 mmol) of tetrakis(triphenylphosphine)palladium (0) and 1.42 g (8.5 mmol) of 3-nitrobenzeneboronic acid. The reaction medium is heated for 2 hours at 70° C. and is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on an RP 18 reverse-phase column, eluting with an acetonitrile/water mixture (1:9). 1.5 g of compound are obtained in sodium sulphonate form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:19][NH:18][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=Cc1ccc(F)cc1)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Fc1ccc(C2C=C(c3cccs3)NN2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
3-(4-Fluorophenyl)-1-(2-thienyl)-2-propen-1-one (3.5 g, 15 mM) and hydrazine hydrate (1.5 g, 30 mM) were added to ethanol (30 ml) and heated under reflux for 3 hours. After the mixture was allowed to cool to room temperature, the solvent was distilled off to obtain 3.6 g (98%) of the desired 5-(4-fluorophenyl)-3-(2-thienyl)-pyrazoline in the form of a pale-yellow oil, nD20=1.6364.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][CH2:24][C:25](=O)[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:17]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1c(F)cccc1Cl
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl

Procedure:
Prepared according to the procedure described in Example 8, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(2-chloro-6-fluoro-phenyl)-butan-2-one.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:11][CH2:10][N:9]2[CH:12]=[C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[N:23]=[C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:20]4)[CH:14]=[C:8]2[C:7]1=[O:33]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[N:27]1([C:25]([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[C:15]([C:13]4[CH:14]=[C:8]5[C:7](=[O:33])[NH:6][CH2:11][CH2:10][N:9]5[CH:12]=4)[CH:16]=[CH:17][CH:18]=3)[N:23]=2)=[O:26])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: COc1ccc(CN2CCn3cc(-c4cccc5ccc(C(=O)N6CCOCC6)nc45)cc3C2=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCn2cc(-c3cccc4ccc(C(=O)N5CCOCC5)nc34)cc21
Yield: 31 %

Procedure:
The above-obtained brown solid 2-(2,4-dimethoxybenzyl)-7-(2-(morpholine-4-carbonyl)quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (Example 167c) in 1 mL of TFA and 1 mL of DCM was heated in an oil bath at 50° C. for 1 h. The mixture was concentrated under reduced pressure. The orange residue was partitioned between 50 mL of EtOAc and 5 mL of 2 N NaOH. The EtOAc layer was washed with 10 mL of brine and concentrated. Purification of the brown residue on a silica gel column (1-10% MeOH in EtOAc) gave 7-(2-(morpholine-4-carbonyl)quinolin-8-yl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (80 mg, 0.213 mmol, 31% yield for 3 steps) as a tan crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (1H, d, J=8.6 Hz), 8.07 (1H, dd, J=7.3, 1.3 Hz), 7.94 (1H, d, J=1.6 Hz), 7.86 (1H, m), 7.75 (2H, d, J=8.4 Hz), 7.67 (1H, t, J=7.7 Hz), 7.36 (1H, d, J=1.8 Hz), 4.23 (2H, m), 3.75 (4H, m), 3.64 (4H, m), 3.57 (2H, m). m/z (ESI, +ve) 377.0 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N([SiH3:18])C(C)C)(C)C>>[CH:1]([N:4]([SiH3:18])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)NC1CCCCC1
Reactant: CC(C)N([SiH3])C(C)C
Product: CC(C)N([SiH3])C1CCCCC1
Yield: 16.7 %

Procedure:
In a 500 ml Schlenk flask 247.3 g (1.75 mol) N-isopropylcyclohexylamine and 229.9 g (1.75 mol) di-isopropylaminosilane were refluxed for 8 days under nitrogen. The byproduct di-isopropylamine was removed with vacuum at a pressure of 40 mmHg and 50° C. Fractional vacuum distillation provided 50 g of pure N-isopropylcyclohexylaminosilane. The normal boiling point (measured at 1 atmosphere) is about 199° C. measured by differential scanning calorimetry (DSC). The end-product was characterized by mass spectroscopy (MS) which is provided in FIG. 1 with peaks at 171 (M+), 156 (M-CH3).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 7 °C

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235 mmol, Intermediate 4: step a), dichloromethane (493 mL), and N,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After the mixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6 mmol) was added such that the addition temperature did not exceed 16° C. After the addition, the reaction was allowed to warm to room temperature. The reaction was then transferred to a reparatory funnel and the organic layer was washed with saturated aqueous NaHCO3 (2×100 mL) followed by water (100 mL) and then dried over sodium sulfate and filtered. Removal of solvent afforded a brown oil as the title compound.
Reaction SMILES: O=[C:2]([CH2:24][CH2:25][C:26](=O)[C:27]1[S:28][C:29]([CH2:32][O:33]C2CCCCO2)=[CH:30][N:31]=1)[CH:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])(=O)C.[NH4+:45]>C(O)(=O)C.C(OCC)(=O)C>[OH:33][CH2:32][C:29]1[S:28][C:27]([C:26]2[NH:45][C:2]([CH:3]([C:11]3[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:13][CH:12]=3)[CH2:4][CH:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[CH:24][CH:25]=2)=[N:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 4-[2,5-dioxo-1-(tetrahydro-2H-pyran-4-ylmethyl)-5-{5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-2-yl}pentyl]benzoate (2.24 g) in acetic acid (15 mL) was added ammonium acetate (4.85 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was m washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.30 g, yield 71%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 469 (MH+).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH3:26])[CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][NH:21][CH2:22]3)[CH2:18]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[F:37].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:15][CH2:16][N:17]2[CH2:24][CH:23]3[O:25][CH:19]([CH2:20][N:21]([CH2:28][CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[CH2:22]3)[CH2:18]2)[CH3:26])(=[O:13])=[O:12])=[CH:7][CH:6]=1)#[N:4]
Reactant: Fc1ccccc1OCCBr
Reactant: CN(CCN1CC2CNCC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCN1CC2CN(CCOc3ccccc3F)CC(C1)O2)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 160 °C
Yield: 58 %

Procedure:
To 4-cyano-N-methyl-N-[2-(9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethyl]-benzenesulfonamide dihydrochloride (0.127 g, 0.30 mmol, prep I above), 1-(2-bromo-ethoxy)-2-fluoro-benzene (0.069 g, 0.315 mmol;) and potassium carbonate (0.145 g, 1.05 mmol) was added acetonitrile (4 mL) and water (0.1 mL). The mixture was heated by microwave irradiation (10 minutes, 160° C.) and was then filtered and evaporated. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 85 mg (58.0%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([O:14][CH3:15])[N:13]=2)[CH:3]=1)[CH3:32]
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1

Procedure:
By proceeding in a similar manner to Example 6(b) but using [6-(3-amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [169 mg, Example 2] and ethyl chloroformate (47 μL), and subjected the reaction product to flash column chromatography on silica gel (10 g) eluting with 20 to 40% EtOAc in heptane) there is prepared (3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-carbamic acid ethyl ester [40.1 mg, 23%, Example 6(c)]. LCMS: RT=2.84 minutes, MS: 423 (M+H).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].[Cl:23][C:24]1[N:25]=[N:26][C:27](Cl)=[CH:28][CH:29]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:27]2[N:26]=[N:25][C:24]([Cl:23])=[CH:29][CH:28]=2)[CH:10]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc(Cl)nn2)c1
Yield: 58.8 %

Procedure:
To a dimethylformamide (8.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (928 mg, 6.1 mmol) was added potassium t-butoxide (750 mg, 6.7 mmol). Upon stirring the reaction at room temperature for 15 min, 3,6-dichloro-pyridazine (1.0 g, 6.7 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (950 mg).
Reaction SMILES: [C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([O:3]CC1C=CC=CC=1)=[O:2].C(O)C.[H][H].[ClH:22]>C(OCC)(=O)C.[Pd]>[ClH:22].[C:1]([CH2:11][N:12]1[CH2:16][CH2:15][N:14]=[CH:13]1)([OH:3])=[O:2]
Reactant: O=C(CN1C=NCC1)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CN1C=NCC1

Procedure:
A suspension of 10.9 g. (0.05 mole) of N-carbobenzyloxymethylimidazoline and 50 mg. of 5% palladium-on-charcoal in 100 ml. of ethanol is shaken in an atmosphere of hydrogen at atmospheric pressure. When the theoretical amount of hydrogen has been absorbed, the spent catalyst is filtered and the filtrate treated with one equivalent of hydrogen chloride dissolved in ethyl acetate. The resulting solution is then concentrated to dryness in vacuo and the residual product triturated with ether and filtered.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH2:8][N:7]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6]1)=O.C([NH2:26])=O.C[O-].[Na+]>CN(C=O)C>[CH2:17]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C@H:5]([C:3]([NH2:26])=[O:2])[CH2:6]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NC=O
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
A solution of (3S,4R)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (62.82 g, 190.5 mmol) and formamide (22.7 mL, 571.4 mmol) in DMF (75 mL) was heated to 100° C. Then sodium methylate solution (5.4 M in methanol, 17.6 mL, 95.2 mmol) was added dropwise over a period of 50 min. The solution was stirred for 3 h at 100° C. (after 1 h further formamide (11.4 mL, 285.7 mmol) was added). The reaction mixture was cooled to ambient temperature and the resulting suspension was separated between ethyl acetate (1500 mL) and water (1000 mL). The organic layers were washed with brine (500 mL), combined and dried over sodium sulfate. Concentration and trituration with tert-butylmethylether (500 mL) afforded the tittle compound (51.19 g, 85%) as white crystals. MS m/e: 315.2 and 317.3 [M+H]+).
Reaction SMILES: [OH:1][CH:2]1[CH2:23][CH2:22][C:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][CH:3]1[O:24][CH2:25][C:26]([F:29])([F:28])[F:27].C(O)(C)C>CCCCCCC>[OH:1][C@@H:2]1[CH2:23][CH2:22][C@:5]2([C:9](=[O:10])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:4][C@H:3]1[O:24][CH2:25][C:26]([F:29])([F:27])[F:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCC(O)C(OCC(F)(F)F)C2
Solvent: CC(C)O
Solvent: CCCCCCC
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CC[C@@]12CC[C@@H](O)[C@H](OCC(F)(F)F)C2
Yield: 28 %

Procedure:
rac-(5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoroethoxy)-2-(4-(trifluoromethoxy)phenyl)-2-azaspiro[4.5]decan-1-one (25 mg, obtained in example 6) was subjected to resolution by preparative HPLC (Chiralpack AD, 30% isopropanol in heptane) to provide (5R,7R,8R)-8-hydroxy-7-(2,2,2-trifluoro-ethoxy)-2-(4-trifluoromethoxy-phenyl)-2-aza-spiro[4.5]decan-1-one (7 mg), MS (ESI): 428.2 (MH+),
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 mL, 0.47 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL). This mixture was then washed with sat. NaHCO3 (50 mL). The aqueous washes were further extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with some residual starting material. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave a residue after concentration of the appropriate fractions in vacuo. This residue was dissolved in a small amount of CH2Cl2 and trituration with diethyl ether gave a solid that was collected by filtration and dried in vacuo to give the title compound (106 mg, 48%) as a cream solid; 1H NMR: 2.27 (3H, s), 2.57 (4H, br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s), 7.52 (1H, d), 7.88 (1H, br s), 8.02 (1H, s), 8.48 (1H, s), 8.67 (1H, s), 9.03 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 523.27.