Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]1)=[CH:11][CH2:10]3)[OH:2].C1(N=C=NC2CCCCC2)CCCCC1.[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1>ClCCl>[Cl:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([O:22][C@H:14]2[CH2:15][CH2:16][C@@:17]3([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]4[C@@H:19]3[CH2:20][CH2:21][C@@:4]3([CH3:5])[C@H:6]4[CH2:7][CH2:8][C:3]3=[N:1][OH:2])[CH2:13]2)=[O:44])=[CH:41][CH:40]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc(Cl)cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.4 %

Procedure:
To the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml), 4-chlorobenzoic acid (0.26 g, 1.6 mmol) was added. The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered and the solvent removed under vacuum. The resulting residue was crystallized from ethyl acetate:petroleum ether (60:80) to give 17-oximino-5-androsten-3β-yl 4-chlorobenzoate (10) (0.30 g, 60.0%) mp 167-170° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:37][N:38]([CH3:42])[C:39]([NH2:41])=[O:40].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:37][N:38]([CH3:42])[C:39](=[O:40])[NH:41][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)C(N)=O
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)N(C)C)c2)cc1F
Yield: 36.3 %

Procedure:
Using the procedure of Example 4, N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol), N,N-dimethylurea (0.102 g, 1.163 mmol), Cs2CO3 (0.158 g, 0.485 mmol), Xantphos (0.034 g, 0.058 mmol), Pd2(dba)3 (0.023 g, 0.025 mmol), and dioxane (5 mL) were combined to afford N-(4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (40 mg, 36.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1H), 8.92 (s, 1H), 8.31 (dd, J=12.6, 7.2 Hz, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.52-7.46 (m, 3H), 7.41-7.33 (m, 3H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.28 (q, J=7.0 Hz, 2H), 2.87 (s, 6H), 1.33 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 568.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC(OC(C)C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27](=[O:30])[N:26]([CH3:31])[N:25]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cn1nc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)ccc1=O
Agent: CC(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(=O)n(C)n4)ncnc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A mixture of 4-[4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 102; 120 mg, 0.28 mmol), trifluoroacetic acid (1.1 mL) and dichloromethane (5.5 mL) was stirred at room temperature for 30 min. The volatiles were evaporated under high vacuum and the residue was dissolved in dichloromethane (6 mL). Isopropyl chloroformate (1 M in toluene; 0.42 mL, 0.42 mmol) and triethylamine (254 μL, 1.8 mmol) were added and the mixture was stirred overnight at room temperature. 1 M aqueous sodium carbonate and dichloromethane were added, and the aqueous layer was extracted three times with dichloromethane. The combined organic extracts were evaporated and the residue was purified by column chromatography on silica gel, eluting with 0-4% methanol/dichloromethane, to give 4-[4-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (79 mg, 68%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.27 (d, 6H, J=6.0 Hz), 2.01 (d, 2H, J=10.9 Hz), 2.11-2.39 (m, 2H), 3.01 (t, 2H, J=12.8 Hz), 3.76 (s, 3H), 4.35 (br s, 2H), 4.85-5.06 (m, 2H), 7.07 (d, 1H, J=10.0 Hz), 7.23 (d, 1H, J=10.0 Hz), 8.17 (s, 1H), 8.51 (s, 1H). Mass spectrum (ES) MH+=414. HRMS Calcd. for C19H24N7O4 (MH+): 414.1885. Found: 414.1884.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])C)[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.[C:17](Cl)(=[O:19])C.COC1C=CC=C2C=1CC[C@H](C)N2.BrC1C=CC2N(C(C3CC3)=O)[C@@H](C)CCC=2C=1O.C1(C(Cl)=O)CC1>>[Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:19][CH3:17])=[O:14])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Reactant: CC(=O)Cl
Agent: COc1cccc2c1CC[C@H](C)N2
Agent: C[C@H]1CCc2c(ccc(Br)c2O)N1C(=O)C1CC1
Agent: O=C(Cl)C1CC1
Product: COC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C

Procedure:
Methyl (S)-6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized following the procedure for (5)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone substituting methyl chloroformate for acetyl chloride in Step 5 or from (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline following the procedure used for the synthesis of (2S)-6-bromo-1-cyclopropanecarbonyl-2-methyl-1,2,3,4-tetrahydroquinolin-5-ol, substituting methyl chloroformate for cyclopropanecarbonyl chloride. MS: (ES, m/z): 300, 302 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1.[Cu][C:16]#[N:17].[NH4+].[OH-].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH:10]1([S:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[N:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1ccc(CSC2CCCC2)cn1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CSC2CCCC2)cn1
Temperature: 25 °C
Yield: 208.2 %

Procedure:
Set up reaction in 3 separate flasks. To flask number 1 slurry 2-chloro-5-cyclopentylthiomethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number 2 slurry 2-chloro-5-cyclopentylthiolmethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number 3 slurry 2-chloro-5-cyclopentyl-thiomethyl-pyridine (2 g, 8.8 mmol) and copper(I) cyanide (1.6 g, 17.6 mmol) in DMF (10 mL). Stir each reaction in a sealed flask at 170° C. for 16 h. Follow the reactions by GC/MS. Cool all reaction flasks to room temperature. Combine the flask contents and pour into a solution of NH4OH (120 mL) and hexane/EtOAc (1:1, 100 mL). Collect the organic phase and extract the aqueous phase twice with hexane/EtOAc (1:1, 100 mL). Concentrate in vacuo the combined organic extracts. Purify by chromatography on silica gel (90 g) eluting with hexane/EtOAc (49:1 to 4:1 gradient) to obtain the desired intermediate (2 g, 40%) that contains approximately 10% starting material. Use the material in the next step without additional purification. MS (APCI+) m/z: 218 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4cccc(F)c4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(-c3cccc(F)c3)c(Cl)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
5-Chloro-4-(6-chloro-3′-fluoro-4-(pyridazin-4-yl)biphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 97, 60 mg, 0.08 mmol) was dissolved in a 4M solution of HCl in dioxane (5 mL). The reaction was stirred for 18 hours at room temperature and then evaporated in vacuo. The residue was dissolved in ethyl acetate (5 mL) washed with water (2×5 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with dichloromethane:methanol:acetic acid (97:2.7:0.3) to give 30 mg of the title compound. The compound was further purified by preparative HPLC to give the title compound (3.6 mg, 7.5%) as a solid.
Reaction SMILES: Cl[Ge:2]([CH3:17])([Ge:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[Ge:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][CH3:5].[OH-:18].[Na+]>O>[O:18]([Ge:2]([CH3:17])([Ge:10]([CH2:13][CH3:14])([CH2:15][CH3:16])[CH2:11][CH3:12])[Ge:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:8][CH3:9])[Ge:2]([CH3:17])([Ge:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[Ge:3]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:4][CH3:5]
Reactant: CC[Ge](CC)(CC)[Ge](C)(Cl)[Ge](CC)(CC)CC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC[Ge](CC)(CC)[Ge](C)(O[Ge](C)([Ge](CC)(CC)CC)[Ge](CC)(CC)CC)[Ge](CC)(CC)CC

Procedure:
This compound was prepared according to the process described in Example I, starting from 3.0 g of 2-chloro-2-methylhexaethyltrigermane, 0.6 g of sodium hydroxide and 3 ml of water. 3.1 g (55%) of colorless, liquid oxybis(1,1,1,3,3,3-hexaethylmethyltrigermane) were obtained; nD20 =1.5410.
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[CH3:16][NH2:17]>>[CH3:16][NH:17][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CN
Product: CNC(=O)c1ccc2c(N)cccc2n1
Temperature: 25 °C

Procedure:
76 mg (0.376 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is dissolved with 10 ml of a 2.0 M methanolic methylamine solution. After 90 minutes under reflux and another 16 hours at room temperature, the solvent is removed under reduced pressure, and the residue is purified on silica gel with hexane-ethyl acetate (0–80%). 72 mg (95% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].CC(=O)CC.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1>[CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C:7](=[CH:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21]
Reactant: C[C@]12CC[C@H]3C(=CC=C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCC(C)=O
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C=C1CC=C1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of androst-5,7-diene-3β,17β-diol (2.9 g, 10 mmol) in 150 ml toluene is azeotropically dried for one hour. Butanone (15 ml) is added followed by aluminum isopropoxide (1.7 g, 8 mmol) and the mixture is heated at reflux for 2.5 hours. The solution is then concentrated to a volume of 25 ml, diluted with trichloromethane, and washed with 5% hydrochloric acid, aqueous sodium bicarbonate, and brine. Concentration and chromatography affords androst-4,7-diene-3,17-dione.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].CS(O[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:24]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3F)C=CC2=O)CC1)(C)(C)C>>[C:33]([O:32][C:30](=[O:31])[NH:29][CH:26]1[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:24][CH2:25]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (500 mg, 2.8 mmol) was deprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (3.3 mmol) as described for Intermediate 20. Colorless solid, 637 mg (57%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]([Sn](CCCC)(CCCC)CCCC)=[CH2:10].[Li+].[Cl-].CCN(C(C)C)C(C)C.[F-].[K+]>CN(C=O)C.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>[CH:9]([C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)=[CH2:10]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cnc(N)cn1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a mixture of 5-bromopyrazin-2-amine (1.0 g, 5.78 mmol) and vinyltri-n-butyltin (2.01 g, 6.36 mmol) in DMF(19 mL) were added LiCl (269 mg, 6.36 mmol) and DIEA (1.1 mL, 6.36 mmol). After degassing for 20 minutes, Pd(PPh3)4 (400 mg, 0.35 mmol) was added to the reaction mixture. And then the mixture was refluxed for 4 hours under Ar atmosphere. The reaction mixture was cooled to room temperature and stirred with a 10% aqueous solution of potassium fluoride for 1 hour. The resulting solution was filtered through a pad of celite and washed with ethyl acetated. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (30% to 50% Ethyl acetate/Hexane) to afford title product (540 mg, 77% yield). MS m/z: 122 [M+1].
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH:19]([C:20](OC)=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[BH4-]>CCOCC>[C:32]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]([N:10]2[CH:19]([CH2:20][OH:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[CH2:11]2)=[O:9])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C1Cc2c(cccc2-c2ccc(OC)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(-c2cccc3c2CC(CO)N(C(=O)C(c2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.5 %

Procedure:
Methyl 2-Diphenylacetyl-5-(p-methoxyphenyl)1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.47 g, 0.93 mmoles) was placed in 50 ml of ether. LiBH4 (0.10 g, 4.5 mmoles) was added. The reaction was stirred at room temperature for 3 days. The ether was evaporated. Methanol was carefully added to quench the LiBH4. The solution was diluted with water and then extracted with dichloromethane. The extracts were dried over MgSO4 and evaporated. The material was then chromatographed using 0-4% methanol in dichloromethane to give product (0.16 g, 0.33 mmoles) in 35% yield, m.p. 57°-63° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[S:3][C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(-c2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)sc1Br
Yield: 94.8 %

Procedure:
A solution of methyl 2-bromo-5-phenylthiophene-3-carboxylate (11c) (290 mg, 0.97 mmol) and sodium hydroxide (156 mg, 3.90 mmol) in a mixture of ethanol (6 mL) and water (2 mL) was refluxed for 30 minutes. The mixture was concentrated in vacuo. The remained aqueous layer was washed with diethyl ether (5 mL), acidified with 1N hydrochloric acid until pH 3 and was extracted with dichloromethane (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired acid (11d) (260 mg, 0.92 mmol, 95%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>C(O)CC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Cl)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCCN1CCOCC1

Procedure:
To a clear solution of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (60.1 g, 178 mmol) in a mixture of n-propanol/ethyl acetate (600/200 mL) at 30-35° C. was added 3-trifluoromethyl benzoyl chloride slowly with stirring. The reaction mixture became turbid initially and solids were separated after the mixture was stirred at ambient temperature for 3 to 5 hours. The solids were filtered, washed with ii-propanol, and dried in vacuo at 40° C. overnight to produce N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-trifluoromethyl-benzamide as a white solid in 72% yield (as the HCl salt). LCMS m/z (%)=509 (M+H 35Cl, 100), 511 (M+H37Cl, 33) 1H NMR (400 MHz, DMSO-d6) δ: 10.7 (bs, 1H), 8.39-8.44 (m, 2H), 8.01 (d, J=2.61 Hz, 1H), 7.98 (s, 1H), 7.75-7.83 (m, 2H), 7.69 (s, 1H), 7.35 (d, J=9.01, 1H), 4.45-4.65 (m, 2H), 3.79-3.89 (m, 4H), 3.69 (s, 3H), 3.36-3.53 (m, 4H with water), 3.05-3.25 (m, 2H), 2.99-3.05 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][C:15]1[S:16][C:17]2[C:18]([N:28]=1)=[C:19]1[C:24](=[CH:25][CH:26]=2)[CH:23]([CH3:27])[NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][CH:26]=[C:17]5[S:16][C:15]([CH3:14])=[N:28][C:18]5=4)[CH:23]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1nc2c3c(ccc2s1)C(C)NCC3
Product: Cc1nc2c3c(ccc2s1)C(C)N(C(=O)c1cc2ncc(Br)cn2n1)CC3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2,6-Dimethyl-6,7,8,9-tetrahydro-thiazolo[4,5-f]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1([CH3:17])[NH:14][C:13](=[O:15])[NH:12][C:11]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[K+].O>C(#N)C>[C:13]([NH:14][C@:10]([CH3:17])([C:11]([OH:18])=[O:16])[CH2:9][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[NH2:12]
Reactant: CC1(CSCc2ccccc2)NC(=O)NC1=O
Reactant: [OH-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@@](CSCc1ccccc1)(NC(N)=O)C(=O)O
Yield: 66.4 %

Procedure:
First, 5.0 g of 5-benzylthiomethyl-5-methylhydantoin was mixed with 3.6 g of potassium hydroxide and 3 g of water, and the mixture was subjected to reaction at 94° C. to 96° C. for 12 hours. The HPLC analysis (column: COSMOSIL 5C18-ARII (produced by Nacalai Tesque Inc.), mobile phase: acetonitrile/10 mM aqueous potassium dihydrogen phosphate solution=30/70, flow rate: 1.0 ml/min, detection wavelength: 254 nm, column temperature: 40° C.) of the reaction mixture showed the production of 3.56 g yield 66.4%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(Br)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 572 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7](CP(OC)(OC)=O)=[CH:6][CH:5]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CP(=O)(OC)OC)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 5.3 g (17.5 mmol) of 2,2,4,4,7,9,9-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3-d][1,3]-cis-dioxole-6-carbaldehyde and 5.9 g (22.8 mmol) of 4-(Dimethoxy-phosphorylmethyl)-benzoic acid methyl ester in 50 ml of toluene at 0° was added 13.4 ml of 1.7 M (22.2 mmol) potassium-tert-pentyl ate. After 1 h, the reaction was poured into brine, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and adsorbed onto silica gel. The product was purified by flash chromatography (gradient elution: hexane-15% ethyl acetate/hexane) to afford 6.0 g (79%) of 4-[(E)-2-(2,2,4,4,7,9,9)-heptamethyl-3a,4,9,9a-tetrahydro-naphtho[2,3d][1,3]-cis-dioxol-6-yl)-vinyl]-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2.[CH2:15]1COCC1.IC>>[CH3:15][N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Reactant: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc2c(c1)cc(C)n2C
Reaction time: 40 h

Procedure:
To a solution of Methyl 2-methyl-1H-indole-5-carboxylate (1000 mg, 5.29 mmol) in THF (53 ml) KOtBu (723 mg, 6.44 mmol) was added and subsequently Iodomethane (1.05 ml, 16.81 mmol) was added at rt. The reaction mixture was stirred at it for 40 hours. The orange reaction mixture was quenched with water/brine and extracted twice with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford crude methyl 1,2-Dimethyl-1H-indole-5-carboxylate.