Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C:3](O)=[O:4].O>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:3](=[O:4])[O:13][C:8]([C:9]([F:12])([F:11])[F:10])=[N:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C(=O)O)=C(NC(=O)C(F)(F)F)c1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(-c2ccccc2)nc(C(F)(F)F)oc1=O
Yield: 92.6 %

Procedure:
39.3 g of the product of Step B were refluxed in 80 ml of acetic anhydride and maintained at this temperature for 30 minutes and then allowed to cool. The acetic anhydride was expelled under reduced pressure and iced water was added to the residue. The precipitate obtained was separated, washed abundantly with water and then dissolved in ether. The organic solution was dried and concentrated to dryness under reduced pressure to obtain 34 g of the expected product melting at 70° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].[OH-].[K+].C1C[O:17][CH2:16]C1.C(=O)(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl>O.CCOC(C)=O>[O:11]1[C@@H:3]2[CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C@@H:2]2[NH:1][C:16]1=[O:17]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: C1CCOC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1N[C@H]2c3ccccc3C[C@H]2O1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
To a solution of (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (500 mg, 3.35 mmol) in water (20 mL) at 0° C. was added potassium hydroxide (1128 mg, 20.1 mmol) followed by THF (20 mL) and the reaction was stirred at 0° C. for 20 minutes. Bis(trichloromethyl) carbonate (995 mg, 3.35 mmol) was added and the reaction was stirred at 0° C. for 2 hours. The reaction was poured into EtOAc and the organic phase washed with 1N HCl, 1N NaOH and brine. After drying over MgSO4, concentration yielded (3aS,8aR)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (574 mg, 97.8% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[C:25](B(O)O)=[CH:24][N:23]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[C:26]([O:28][CH3:29])=[N:27][C:22]([O:21][CH3:20])=[N:23][CH:24]=3)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ncc(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c(OC)n1
Yield: 39.6 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,4-dimethoxypyrimidin-5-boronic acid (176 mg, 0.96 mmol) were reacted. After purification the title compound (73 mg, 39% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6 ) δ 9.04 (d, J=4.9 Hz, 1H), 8.57 (dd, J=5.6, 9.3 Hz, 1H), 8.37 (s, 1H) 7.77 (t, J=9.1 Hz, 1H), 3.99 (s, 3H), 3.84 (s, 3H), 2.93 (m, 1H), 0.70(m, 4H). MS APCI, m/z=385.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]([Cu])#[N:14]>CN1C(=O)CCC1>[C:13]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 200 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-bromo-4-hydroxybenzoate (2.50 g, 10.8 mmol) and CuCN (1.10 g, 12.3 mmol) in NMP (10 mL) was stirred at 200° C. under N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted in ethyl acetate (100 mL) and washed with water (50 mL×3) and brine (50 mL), then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc=8/1).
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:20][CH2:19][C:16]([CH3:21])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2)(C1C=CC(C)=CC=1)(=O)=O.[C-:22]#[N:23].[Na+].CS(C)=O>C(Cl)Cl>[CH3:21][C:16]12[CH2:15][CH2:14][C:13]([CH2:12][C:22]#[N:23])([CH2:18][CH2:17]1)[CH2:20][CH2:19]2
Reactant: Cc1ccc(S(=O)(=O)OCC23CCC(C)(CC2)CC3)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC12CCC(CC#N)(CC1)CC2

Procedure:
The mixture containing 0.065 mole of 4-methylbicyclo[2.2.2]oct-1-yl methanol tosylate, 0.1 mole of sodium cyanide, and 100 ml. of dimethyl sulfoxide is stirred at 70° C for 4 hours and then poured into 500 ml. of methylene chloride. The organic phase is then washed four times with water, separated and dried with anhydrous magnesium sulfate and filtered. The filtrate is then evaporated under vacuum affording an oil which is then chromatographed on silica gel eluting with 10% ethyl acetate-90%, vol., hexane affording 4-methylbicyclo[2.2.2]oct-1-yl acetonitrile.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br.O>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH2:32][CH2:31][Br:30])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:3]1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1c(S(=O)(=O)c2ccc(O)cc2)c2ccccc2n1C
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1c(S(=O)(=O)c2ccc(OCCCBr)cc2)c2ccccc2n1C
Temperature: 100 °C
Yield: 70.5 %

Procedure:
To a solution of 2.8 g (0.0085 mol) of 1-methyl-2-isopropyl-(4-hydroxy-benzenesulphonyl)indole in 100 ml of N,N-dimethyl formamide were added 14 g of anhydrous and crushed potassium carbonate. After that 6.8 g (0.037 mol) of 1,3-dibromopropane were added and the medium was heated at 100° C. for 0.5 hour. The mixture was poured into water, extracted with ethyl ether and the ethereal fraction was washed with water, dried on anhydrous sodium sulphate, filtered and evaporated to obtain 2.7 g of 1-methyl-3-[4-(3-bromo-propoxy)benzenesulphonyl]-2-isopropyl-indole (yield: 69%). This crude bromopropoxy derivative was dissolved in 60 ml of dimethylsulphoxide and 2.2 g (0.03 mol) of tert-butylamine were added. The medium was then stirred at room-temperature for 48 hours, poured into water and extracted with ethyl ether. The ethereal solution was then washed with water, dried on anhydrous sodium sulphate, filtered and evaporated. The crude product so obtained (2.3 g) was then purified by chromatography on a silica column (solvent:methanol).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([O:4][CH2:5][C@@:6]12[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@@H:18]([OH:24])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]1=[CH:10][C:9](=[O:25])[CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reaction time: 2 h

Procedure:
To a solution of 25.6 g of 19-acetoxyandrost-4-ene- 3,17 -dione in 4 liters of methanol cooled to 0° C is added 3.1 g of sodium borohydride, and the mixture is stirred at 0° C for 1 hour after which 30 ml of acetic acid is added and the methanol removed under reduced pressure. The resulting residue is taken up in ethyl acetate and washed with water. The organic layer is dried over magnesium sulfate, filtered and the solvent removed. The solid residue is dissolved in 2 liters of chloroform treated with 125 g of manganese dioxide and stirred for 2 hours. The reaction mixture is filtered, and the solvent removed under reduced pressure. The residue is chromatographed on alumina using benzene-ether (1:1) as the eluant. The product is recrystallized from acetone-hexane to give 19-acetoxy-17β-hydroxyandrost-4-en-3-one, M.P. 125°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([N:17]([CH3:39])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:30][CH2:29][NH:28][C@@H:27]([CH3:38])[CH2:26]4)=[CH:20][CH:19]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)N3CCC(Nc4cccc(F)c4)CC3)cc2)CCN1
Yield: 80.7 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-({4-[({4-[(3-fluorophenyl)amino]-1-piperidinyl}carbonyl)(methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D33) (67 mg, 0.124 mmol) in DCM (2.5 ml) and TFA (0.5 ml) was stirred at room temp for ˜1.5 h. The solvent was removed in vacuo and the residue partitioned between DCM and saturated aqueous NaHCO3 solution. The aqueous layer was further extracted with DCM and the combined organic layers were dried and concentrated to give the crude product as a pale yellow oil. Column chromatography eluting with 0-10% (2M NH3 in MeOH)/DCM gave the title compound as a pale yellow oil (44 mg). δH (CDCl3, 400 MHz) 7.27 (2H, d), 7.05 (3H, m), 6.34 (1H, m), 6.29 (1H, m), 6.21 (1H, m), 3.77 (2H, d), 3.62 (1H, d), 3.47 (2H, m), 3.38 (1H, m), 3.21 (3H, s), 2.93 (3H, m), 2.75 (3H, m), 2.20 (1H+H2O, br. s), 2.05 (1H, td), 1.85 (2H, m), 1.72 (1H, m), 1.16 (2H, m), 1.04 (3H, d). MS (ES): MH+ 440.2. This whole was dissolved in DCM and treated with 1M HCl in Et2O (100 ul). The solvent was removed in vacuo to give the hydrochloride salt of the title compound as a white solid (47 mg). MS (ES): MH+ 440.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][C:8]=2[CH3:16])=[N:3]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:17][C:2]1([CH3:1])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:14])[CH3:15])=[CH:9][C:8]=2[CH2:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=2)=[N:3]1
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1cc(C(C)C)ccc1C1=NC(C)(C)CO1
Product: Cc1cccc(CCc2cc(C(C)C)ccc2C2=NC(C)(C)CO2)c1

Procedure:
The subtitle compound was prepared from the product of step (ii) and 3-bromomethyltoluene (9.25 g) using the method of example 15 step (iv). Purification was by chromatography eluting with toluene. Yield 4.8 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[K+].[CH2:17]([OH:19])[CH3:18]>C(OCC)(=O)C>[CH2:17]([O:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:18]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCCCCCCCCCC(=O)O
Yield: 35 %

Procedure:
11-bromoundecanoic acid (2.25 g, 8.47 mmol) was added to a solution of potassium hydroxide (2.15 g, 38.3 mmol) in absolute ethanol (20 mL) and refluxed for 7 hrs. After cooling and acidification with HCl, solvent was removed under reduced pressure to give a white solid. The sample was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by silica column chromatography in 1% diethyl ether/0.3% formic acid/methylene chloride. Solvent was removed under reduced pressure to yield 11-(ethoxy)undecanoic acid (680 mg, 35%): mp 44-45.5° C.; 1H NMR (300 MHz, CDC13) δ 1.20 (t, 3H, J=7.0, CH3), 1.24-1.40 (bm, 12H, methylene envelope), 1.52-1.68 (bm, 4H, O-CH2 -CH2 ; CH2 -CH2 -COOH), 2.34 (t, 2 H, J=7.5, CH2 -COOH), 3.41 (t, 2H, J=6.8, O-CH2 -CH2), 3.48 (q, 2H, J=7.0, O-CH2 -CH3), 10.25 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCL3) δ 15.27, 24.75, 26.23, 29.11, 29.26, 29.40, 29.55*, 29.80, 34.12, 66.06, 70.76, 179.71; m/z 231 (M+H+).
Reaction SMILES: Cl[CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C-:17]#[N:18].[Na+].O>CS(C)=O>[C:17]([CH:2]([CH2:15][CH3:16])[CH2:3][CH2:4][C:5]#[C:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)#[N:18]
Reactant: [C-]#N
Reactant: CCC(Cl)CCC#CCOC1CCCCO1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C#N)CCC#CCOC1CCCCO1
Reaction time: 65 h
Yield: 65.8 %

Procedure:
A solution of chloride 35 (20.0 g, 92.3 mmol) in dry DMSO (75 mL) was added to a solution of NaCN (6.0 g, 122.0 mmol) in dry DMSO (100 mL). The reaction mixture was stirred at 50°-60° C. for 65 h. The dark brown mixture was cooled, poured into water (200 mL), and extracted with five 100-mL portions of CH2Cl2. The combined organic extracts were washed with water (3×150 mL), dried over Na2SO4, and concentrated by rotary evaporation. The black oil was dissolved in Et2O (200 mL) and filtered through a pad of silica gel (60-200 mesh, Baker Chemical Co.) to yield 36 as a yellow oil (14.3 g, 75%): IR (neat) 2940 (s), 2870, 2280 (w), 2250, 1440, 1345, 1200, 1130, 1115 (s), 1075, 1020 (s), 900, 865, 810 cm-1 ; 1H NMR (CDCl3)δ 4.80 (m, 1H), 4.23 (t, J=2 Hz, 2H), 3.66 (m, 2H), (m, 4H), 1.67 (m, 8H). Nitrile 36 was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][CH2:6][CH2:5]2.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2
Reactant: O=C1NCCc2cc(Br)ccc21
Solvent: CO
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CCNC2

Procedure:
A solution of 6-bromo-3,4-dihydro-1(1H)-isoquinolinone (Example 31, Step 1; 5.5 g, 1.0 mmol) in THF (25 mL) was treated with 1M BH3 in THF (5 mL, 5 mmol) and heated at reflux for 20 h. To the mixture was added MeOH (5 mL), the solvent removed and the residue heated with 2N HCl for 3 h. The reaction was cooled, made basic with aqueous NH4OH and extracted with CH2Cl2, dried and evaporated to give the title compound as a gum which was used as such.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]([NH2:12])=[S:11].C(=O)([O-])O.[Na+]>C(O)C>[NH2:12][C:10]1[S:11][CH:2]=[C:3]([C:4]([CH3:7])([CH3:6])[CH3:5])[N:9]=1
Reactant: NC(N)=S
Reactant: CC(C)(C)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1csc(N)n1
Yield: 90.9 %

Procedure:
A mixture of 1-bromo-3,3-dimethyl-2-butanone (5.03 g, 28.1 mmol), thiourea (2.35 g, 30.9 mmol) and ethanol (30 mL) was refluxed for 1.5 hours. After cooling, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=2:1→1:1) to give the title compound (3.99 g, 90.9%) as a yellowish white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12](B(O)O)[CH:11]=[CH:10][N:9]=1.FC(F)(F)S(O[C:23]1[CH:36]=[C:35]2[C:26]([O:27][C:28]3[CH:29]=[CH:30][C:31]([C:52]4[C:53]([F:58])=[N:54][CH:55]=[CH:56][CH:57]=4)=[CH:32][C:33]=3[C:34]32[C:40]2=[N:41][CH:42]=[CH:43][N:39]2[C:38]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:37]3)=[C:25]([F:59])[CH:24]=1)(=O)=O>O1CCOCC1.O>[F:59][C:25]1[C:26]2[O:27][C:28]3[C:33](=[CH:32][C:31]([C:52]4[C:53]([F:58])=[N:54][CH:55]=[CH:56][CH:57]=4)=[CH:30][CH:29]=3)[C:34]3([C:40]4=[N:41][CH:42]=[CH:43][N:39]4[C:38]([NH:44][C:45](=[O:46])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[N:37]3)[C:35]=2[CH:36]=[C:23]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([F:7])[CH:13]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(OS(=O)(=O)C(F)(F)F)cc32)c2nccn21
Reactant: OB(O)c1ccnc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(-c4ccnc(F)c4)cc32)c2nccn21
Temperature: 100 °C
Yield: 54.5 %

Procedure:
PdCl2dppf (25.1 mg, 0.031 mmol), potassium carbonate (1232 μL, 1.232 mmol), 2-fluoropyridin-4-ylboronic acid (87 mg, 0.616 mmol), and 5-(tert-butoxycarbonylamino)-5′-fluoro-2′-(2-fluoropyridin-3-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-7′-yl trifluoromethanesulfonate (200 mg, 0.308 mmol) were combined in dioxane/water 4:1 (3079 μL) and heated at 100° C. for 2 hours. The solution was concentrated. The product was purified via silica gel column chromatography using 0-60% EtOAc in hexane to afford tert-butyl 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-5-ylcarbamate (100 mg, 0.168 mmol, 54.4% yield). This material was treated with TFA (0.323 ml, 4.19 mmol) in DCM (2 ml) and stirred at RT for 1 hr. The solution was concentrated, and the racemic residue was separated by SFC using an IC (10×0.46 cm) column, eluting with 20% IPA (DEA)/CO2, 100 bar, 4 mL/min, 220 nm to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example 8A) and (R)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-fluoropyridin-4-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example 8B). Mass Spec is in Table 1.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccncc2)s1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Sc2ccncc2)s1
Yield: 69 %

Procedure:
A mixture of 2-acetylamino-5-(4-pyridylthio)thiazole (4.7 g), acetic acid (35 ml) and 6N-aqueous hydrochloric acid (10 ml) was refluxed for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted pH 8.5 using aqueous sodium bicarbonate under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-pyridylthio)thiazole (2.7 g, yield: 69.5%). mp: 180°-185° C. (dec.) IR (Nujol): 3270, 3150, 1630, 1580, 1380 cm-1
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#[N:14].Cl>O1CCOCC1>[O:9]=[C:7]1[NH:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:1][C:2]2[S:3][C:4]([CH3:12])=[CH:5][C:6]1=2
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: N#Cc1cccnc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc2c(=O)[nH]c(-c3cccnc3)nc2s1
Yield: 95.1 %

Procedure:
5 g of 2-amino-5-methyl-3-ethoxycarbonylthiophene together with 2.7 g of 3-cyanopyridine are dissolved in 40 ml of dioxane. Then, gaseous HCl is passed through the solution for 5 hours. After customary workup, 6 g of 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methylthieno[2,3-d]pyrimidine are obtained.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[Na].O[CH:30]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][O:31]1>CS(C)=O>[OH:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1/[CH:39]=[CH:30]/[CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC1Cc2ccccc2CO1
Agent: [Br-]
Agent: [Na]
Solvent: CS(C)=O
Product: O=C(O)CCCC/C=C/c1ccccc1CO
Reaction time: 1 h

Procedure:
To a solution of 60.2 g. of 4-carboxybutyltriphenylphosphonium bromide in 200 ml. of dimethylsulfoxide is added a solution of the sodium salt of dimethylsulfoxide. The solution is stirred for one hour and 6.8 g. of 3-hydroxyisochromane in 25 ml. of dimethylsulfoxide is added. The solution is stirred at room temperature for 40 hours and then poured into 1200 ml. of ice water and filtered. The filtrate is washed with ether-ethyl acetate (1:1) and acidified to pH2 with oxalic acid. The mixture is again filtered and the filtrate is extracted with ether-pentane (2:1). The extract is washed with brine, dried, concentrated, and the solid recrystallized from toluene to yield 7-(2-hydroxymethylphenyl)trans-6-heptenoic acid as white crystals having a melting point of 92°-94.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.I[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCI
Reactant: OCC1CCCNC1
Product: CCCCCCN1CCCC(CO)C1
Yield: 93.6 %

Procedure:
3-Piperidine methanol (2.30 g, 20 mmol) and 1-iodohexane (1.5 mL, 10 mmol) were converted to product by the procedure of Preparation 1 to yield 1.866 g (47%) of the title compound which was used without further purification. 1H NMR consistent with desired product.
Reaction SMILES: [CH3:1][C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH2:35])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[Cl:25][C:26]1[N:30]2[N:31]=[C:32]([NH:35][C:2](=[O:3])[CH3:1])[CH:33]=[CH:34][C:29]2=[N:28][N:27]=1
Reactant: Nc1ccc2nnc(Cl)n2n1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nnc(Cl)n2n1
Reaction time: 6 h

Procedure:
0.11 cm3 of acetic anhyhdride is added to a mixture of 202 mg of 3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-amine in 5 cm3 of pyridine at 0° C. The temperature is allowed to rise to 20° C. over 6 h, then 0.05 cm3 of acetic anhydride is again added and stirring is maintained for 24 h. The precipitate formed is spin-filter-dried and then washed with ethyl ether and pentane. This solid is purified by chromatography on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μM), elution being carried out with a gradient of dichloromethane/methanol of 100/0 to 90/10. 41 mg of N-(3-chloro[1,2,4]triazolo[4,3-b]pyridazin-6-yl)acetamide are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][O:14][C:15]2[CH:16]=[C:17]([NH2:20])[NH:18][N:19]=2)[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1.C(=O)(OC(C)(C)C)[O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>O.ClCCl>[NH2:20][C:17]1[N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[N:19]=[C:15]([O:14][CH2:13][C:7]2[CH:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
Potassium hydroxide (11.19 g, 199.4 mmol) dissolved in water (44.8 ml) was added to a solution of 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (7.121 g) dissolved in dichloromethane (40 ml). (2-Methylpropan-2-yl)oxycarbonyl tert-butyl carbonate (6.8 g, 31.2 mmol) dissolved in DCM (35 ml) was added and the reaction mixture was stirred vigorously at room temperature for 4 h. The reaction mixture was separated and the organic layer was washed with water (2×15 ml) and brine (2×15 ml), dried over sodium sulphate, filtered, evaporated and dried in vacuo to give tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (8.70 g, 99%) as a cream solid.