Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[NH:26][N:25]=[C:24]([C:27]4[N:28]=[CH:29][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:31]=4)[CH:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9].C(O)=O.C1COCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C@@H:17]([NH:19][C:20]([C:22]3[NH:26][N:25]=[C:24]([C:27]4[N:28]=[CH:29][NH:30][CH:31]=4)[CH:23]=3)=[O:21])[CH3:18])[N:12]=2)[CH:5]=[C:6]([F:10])[C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)n[nH]1
Solvent: O=CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2c[nH]cn2)n[nH]1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
Into (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazole-5-carboxamide (0.139 mmol, 0.095 g) was added 4 ml of a solution containing formic acid (41.8 mmol, 1.926 g), THF (20 ml) and water (1 ml). The resulting mixture was stirred first at RT after which the temperature was raised to 50° C. for 2 h. The solvent was evaporated, ACN was added and evaporated again. This was repeated once more. The crude product was purified by preparative HPLC. 0.0169 g of the title compound was obtained. 1H-NMR (400 MHz, CDCl3): δ 1.27 (d, 3H), 4.14 (dd, 1H), 4.45 (dd, 1H), 4-57-4.64 (m, 1H), 6.29 (bs), 6.63 (d, 1H), 6.90 (s, 1H), 7.32 (d, 1H), 7.51 (d, 1H), 7.52 (s, 1H), 7.63 (dd, 1H), 7.73 (d, 1H), 7.84-7.86 (m, 1H) LC-MS: [M+1]=439.0.
Reaction SMILES: CNC1(C2C=CC=CC=2Cl)C(=O)CCCC1.CC1C=CC=C(C)C=1NC1SCCCN=1.CCCCCCC([O:40][C@@H:41]1[C@@:45]2([CH3:60])[CH2:46][CH2:47][C@@H:48]3[C@:58]4([CH3:59])[C:52](=[CH:53][C:54]([CH2:56][CH2:57]4)=[O:55])[CH2:51][CH2:50][C@H:49]3[C@@H:44]2[CH2:43][CH2:42]1)=O>>[CH3:60][C@@:45]12[C@@H:41]([OH:40])[CH2:42][CH2:43][C@H:44]1[C@@H:49]1[CH2:50][CH2:51][C:52]3[C@@:58]([CH3:59])([C@H:48]1[CH2:47][CH2:46]2)[CH2:57][CH2:56][C:54](=[O:55])[CH:53]=3
Reactant: CCCCCCC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CNC1(c2ccccc2Cl)CCCCC1=O
Agent: Cc1cccc(C)c1NC1=NCCCS1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
Male AR-97Q mice and their normal littermates were castrated or sham-operated via the abdominal route under ketamine-xylazine anesthesia (50 mg/kg ketamine and 10 mg/kg xylazine, i.p.) at 4 weeks of age. Female AR-97Q mice and their littermates were subcutaneously injected 20 μg of testosterone enanthate dissolved in 20 μl of sesame oil weekly from 4 weeks of age until the end of the analysis. The control mice were given the same amount of sesame oil.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[CH3:27][N:28](C)[C:29]#N>C1COCC1>[CH3:27][N:28]([CH3:29])[C:15]1[N:3]=[C:4]([OH:14])[C:5]2[C:6]([CH:16]=1)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Reactant: CN(C)C#N
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1000 mg, 4.52 mmol) in THF (10 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (5316 μl, 9.04 mmol) and the solution was stirred for 0.5 h before addition of N,N-dimethylcyanamide (317 mg, 4.52 mmol) in THF (10 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl, and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate, filtered, followed by removal of solvent under vacuum to give 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 71% yield) which was carried to the next step without further purification. MS: MS m/z 219.1 (M++1).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([C:31](Cl)=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:32])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(NC(=O)c2cccc3ccccc23)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (369 ml, 2.45 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (622 mg, 89%).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C1COCCN1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCOCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with morpholine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-morpholin-4-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 505 (MH+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH2:4][CH2:3]1.[Cl:6][C:7]([Cl:12])(Cl)[C:8](Cl)=[O:9]>CCOCC.[Zn]>[Cl:6][C:7]1([Cl:12])[C:2]2([CH2:5][CH2:4][CH2:3]2)[CH2:1][C:8]1=[O:9]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: C=C1CCC1
Agent: [Zn]
Solvent: CCOCC
Product: O=C1CC2(CCC2)C1(Cl)Cl
Reaction time: 4 h

Procedure:
Methylenecyclobutane (5.00 g, 70.5 mmol) and zinc dust (13.8 g, 211 mmol) were suspended in dry Et2O (200 mL) in a 3 necked round bottomed flask having an addition funnel and reflux condenser and placed in a sonic bath at 25° C. The system was sonicated and 2,2,2-trichloroacetyl chloride (10.282 mL, 91.607 mmol) (as a solution in 50 mL dry Et2O) added drop-wise, during which time the reaction became warm and the Et2O began refluxing). The sonication was continued for 4 hours. The reaction mixture was filtered through a pad of Celite® and the organic layer was washed sequentially with NH4Cl, NaHCO3 and brine. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to afford the crude material, which was in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:23](=O)[NH:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:23]1[N:12]2[CH:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][O:15][C:16]3=[C:11]2[C:10](=[CH:9][CH:8]=[C:7]3[C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:26])[N:24]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1ccccc1
Product: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Temperature: 95 °C
Yield: 99.8 %

Procedure:
To 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (40.0 mg, 0.115 mmol) in a vial, phosphoryl chloride (1.5 mL, 16 mmol) was added and the mixture was heated at 95° C. overnight. The mixture was evaporated and extracted with EtOAc. The extracts were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. Filtration and evaporation gave the desired compound (42 mg, 100%). LCMS calc. for C20H17ClN3O2 (M+H)+: m/z=366.1. found: 366.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[S-:13][C:14]#[N:15].[K+].O>C(O)C>[C:8]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:13][C:14]#[N:15])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CSCC(=O)c1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 3-(bromoacetyl)benzonitrile (7.72 g, 34.5 mmol) and potassium thiocyanate (3.35 g, 34.5 mmol) in ethanol (70 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (70 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 4.39 g (63.0% (2 steps)) of the desired product as a solid.
Reaction SMILES: [B].C[O:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][CH2:16][C@H:15]2[CH2:14][N:13]([CH3:26])[CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[NH4+].[OH-]>C(Cl)(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][CH2:16][C@H:15]2[CH2:14][N:13]([CH3:26])[CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@]23CCN(C)C[C@@H]2CC=C(c2ccccc2)C3)c1
Agent: [B]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN1CC[C@]2(c3cccc(O)c3)CC(c3ccccc3)=CC[C@H]2C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.1 %

Procedure:
2.7 ml (29 mmol) of boron uibromide were dissolved in 85 ml of dry CHCl3 under a nitrogen atmosphere. 1.6 g (4.8 mmol) of (±)-trans4a-(3-methoxyphenyl)-2-methyl-6-phenyl-1,2,3,4,4a,5,8,8a-octahydroisoquinoline dissolved in 17 ml of dry CHCl3 were added dropwise at room temperature. After 2 h the reaction mixture was poured onto 85 g of crushed ice containing 8.5 ml of conc. NH4OH and stirred 20 min. The phases were separated, the organic phase was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by flash chromatography, eluting with a mixture CH2Cl2 /MeOH/conc. NH4OH 82:13:0.8 respectively. The resulting solid was triturated with acetone, filtered, washed and dried, yielding 0.6 g of the title compound. M.p.=243-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[N:31]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([S:18]([N:41]2[CH2:40][CH2:39][N:38]([CH2:37][CH2:36][N:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[CH2:43][CH2:42]2)(=[O:20])=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29]
Reactant: C1CCN(CCN2CCNCC2)C1
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(S(=O)(=O)Cl)cc2N1c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCc2c(-c3ccccc3Cl)cc(S(=O)(=O)N3CCN(CCN4CCCC4)CC3)cc2N1c1c(Cl)cccc1Cl

Procedure:
The 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-{[4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl]sulfonyl}-3,4-dihydroquinazolin-2(1H)-one was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-sulfonyl chloride and 1-(2-pyrrolidin-1-ylethyl)piperazine by a procedure analogous to that described in EXAMPLE CCC23, STEP A, except that no diisopropylethylamine was used. Mass spectrum (ESI) 648 (M+1). 1H NMR (500 MHz, CDCl3): selected peaks δ 1.81 (brs, 4H); 2.58 (m, 12H); 3.00 (brs, 4H); 4.35 (dd, J=15.4 Hz, J=1.6 Hz, 1 H); 4.46 (dd, J=15.4 Hz, J=1.6 Hz, 1H).
Reaction SMILES: COC1C=C2C(=CC=1)C=C(C1C=CC=CC=1N)C=C2.Cl.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:25](O)=O.FC1C=[C:43](C=CC=1OCCN1CCCCC1)[CH2:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH:53]=1>>[CH2:44]([N:45]([CH2:25][C:24]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:22]([F:21])[CH:23]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH:53]=1)[CH3:43]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc2cc(-c3ccccc3NCc3ccc(OCCN4CCCCC4)c(F)c3)ccc2c1
Agent: COc1ccc2cc(-c3ccccc3N)ccc2c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1ccccc1-c1ccc2cc(OC)ccc2c1

Procedure:
Synthesized from 2-(6-methoxynaphthalen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxynaphthalen-2-yl)phenyl]amine (362 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][2-(6-methoxynaphthalen-2-yl)phenyl]amine (310 mg). This compound (308 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (205 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21]Cl)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.N12CCCCC1C=NCCC2.O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([C:19]#[C:20][CH2:21][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCCl)cc12
Agent: C1=NCCCN2CCCCC12
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C#CCN3CCCCC3)cc12
Yield: 28.3 %

Procedure:
156 mg of 6-(3-chloro-1-propinyl)-beta-carboline-3-carboxylic-acid-ethylester is stirred together with 85 mg of piperidine and 76 mg of 1.5-diazabicyclo-[5.4.0]undec-5-ene in 10 ml of absolute ethanol under nitrogen and exclusion of water for 11/2 h at 60° C. After evaporation, the residue is chromatographed on 25 g of silica gel with methylene-chloride/methanol (10/2) as the eluant. 51 mg of 6-[3-(1-piperidinyl)-1-propinyl]-beta-carboline-3-carboxylic-acid-ethylester is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14])([O-:3])=[O:2].[CH3:17][NH:18][CH2:19][CH2:20][OH:21]>O1CCCC1>[OH:21][CH2:20][CH2:19][N:18]([CH3:17])[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=1)=[O:12]
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 71.1 %

Procedure:
To a solution of 46.4 g (0.2 mol) of 4-nitro-3-(trifluoromethyl)phenyl isocyanate in 200 ml of tetrahydrofuran was added dropwise with stirring and external cooling 15.2 g (0.2 mol) of 2-(methylamino)ethanol. This addition was exothermic. The solution was concentrated under reduced pressure, washed with water, acidified with hydrochloric acid and extracted with ether. Crystallization of the ether extract gave 43.69 g (71% yield) of the desired product as a tan solid; m.p. 180°-181° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:25])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
To a solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-(2,2,2-trichloro-ethyl) ester (5.0 g, 10.8 mmol) in tetrahydrofuran/methanol (50 mL, 1:1) containing 3 Å molecular sieves at 0° C. was added tetra n-butylammonium fluoride (22 mL, 22 mmol, 1 M in tetrahydrofuran). After stirring at room temperature for 24 h, the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was partitioned between diethyl ether and saturated sodium hydrogen carbonate solution. The aqueous layer was extracted with diethyl ether. The organic extracts were combined and the solution was filtered through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with iso-hexanes/ethyl acetate 20:1 to 3:2 to afford (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 82%) as a colorless oil and as a mixture of rotamers. LCMS (m/z) 345.1 [M+H], Tr=2.78 min. A solution of (S)-tetrahydro-pyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester 3-methyl ester (3.0 g, 8.72 mmol) in tetrahydrofuran (20 mL) at −78° C. was treated with lithium bis(trimethylsilyl)amide (13 mL, 13.0 mmol, 1 M in tetrahydrofuran). After stirring at −78° C. for 1 h, the mixture was treated with iodomethane (1.4 mL, 22.5 mmol). The reaction mixture was stirred at −78° C. for 1 h, then at 0° C. for 1 h and at room temperature for 1 h. The reaction mixture was re-cooled to 0° C. and quenched with water. The aqueous phase was extracted with dichloromethane (2×) and the organic solution was passed through a hydrophobic frit and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of iso-hexanes/ethyl acetate 4:1 to 0:1 to afford the title compound (1.62 g, 52%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.41-1.52 (m, 18H), 1.53-1.67 (m, 4H), 1.71-1.99 (m, 3H), 3.17-3.51 (m, 1H), 3.70-3.81 (m, 3H), 3.90-4.21 (m, 1H). LCMS (m/z) 359.0 [M+H], Tr=2.90 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[OH-].[Na+:16].[Na]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O-:11])=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[Na+:16]
Reactant: Cn1cc(C=CC(=O)O)c([N+](=O)[O-])n1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Product: Cn1cc(C=CC(=O)[O-])c([N+](=O)[O-])n1

Procedure:
197 mg. 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid (prepared according to Example 1) are neutralized with a dilute aqueous solution of sodium hydroxide. The clear solution is evaporated to dryness and the residue is triturated with isopropanol. After filtering off with suction and washing with diethyl ether, there are obtained 170 mg. of the desired sodium salt; m.p. 306° (with foaming).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:37][CH2:38][CH3:39])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([CH3:36])([CH3:35])[C:28]([O:30]C(C)(C)C)=[O:29])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>O>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:37][CH2:38][CH3:39])=[C:16]([CH:23]4[CH2:26][N:25]([C:27]([CH3:35])([CH3:36])[C:28]([OH:30])=[O:29])[CH2:24]4)[C:17]([C:21]#[N:22])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)O)C1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoate (0.36 g, 0.65 mmol, chiral intermediate from Example 236) was dissolved in a premixed solution of trifluoroacetic acid (3.2 mL)/water (0.065 mL) and stirred at room temperature for 3 h and at 50° C. for 30 min. The reaction mixture was concentrated and reconcentrated from acetonitrile (2×) to give the desired product as a gum. This gum was treated with a small amount of methyl-tert-butylether that was swirled until a solid formed. The methyl-tert-butylether was decanted and the residue was concentrated to give the desired product (0.51 g, 109%) that was used without further purification. LCMS for C24H29ClN7O3 (M+H)+: m/z=498.2; Found: 498.3.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]2.[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([CH3:31])[CH:25]=[CH:24]3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: Cc1ccc2cc(CCl)ccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2ccc3nc(C)ccc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 47022 (409 mg, 1.7 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 6-(chloromethyl)-2-methylquinolinehydrochloride SLA 47080B (400 mg, 1.7 mmol) and a 2 N aq. LiOH solution (1.75 mL, 3.5 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was removed at 40° C. under vacuum and the residue was taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 93:7) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 93:7) provided 1-ethyl-6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((2-methylquinolin-6-yl)methyl)isoquinolin-3-ol dihydrochloride 81 as a yellow solid (66 mg, 8% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].CN(CCN)C.COC1C=C(N2CCNCC2)C=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:23][CH3:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Agent: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)NCCN(C)C)CC2)c1
Yield: 51 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 5.8 g (0.03 mole) of 1-(3-methoxyphenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil which solidified. After trituration with petroleum ether (30°-60° C.), the collected solid was recrystallized from cyclohexanebenzene to yield 4.7 g (51%) of the title compound as a white crystalline solid, m.p. 70°-72° C.