Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Cl[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[NH:21]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[O:12][C:25]1[N:20]=[N:21][C:22]([Cl:26])=[CH:23][CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC1=CC=CN(Cl)N1
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cccc(C(C)(C)C)c1Oc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
17.5 g (107 mmol) of 2-tert-butyl-6-methylphenol, 11.9 g (106 mmol) of potassium tert-butoxide and 1,4-dioxane (250 mL) were mixed, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 15.0 g (101 mmol) of 2,6-dichloropyridazine and the resulting mixture was stirred at 100° C. for 3 hours and 15 minutes. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was crystallized form isopropyl ether to obtain 15.3 g (55.2 mmol, Yield: 54.6%) of 3-(2-tert-butyl-6-methylphenoxy)-6-chloropyridazine.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:9]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1)=[C:8]2[O:31][CH:32]([F:33])[F:34]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(S(C)(=O)=O)cc3)c(OC(F)F)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [8-chloro-4-difluoromethoxy-2-isopropyl-3-(4-methanesulfonylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.040 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.10 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue diluted with water and then the pH adjusted to 5 by the addition of sodium dihydrogenphosphate. The mixture was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and then the solvent removed under reduced pressure to afford title compound, 0.025 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.[CH3:29]I.[H-].[Na+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][O:25][CH3:29])[CH:17]=4)=[N:14][N:13]([CH3:26])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(-c2nn(C)c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 23.4 %

Procedure:
4-(7,8-Dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (17 mg, 44 μmol) is dissolved in N,N-dimethylformamide (2.1 ml) under argon, and methyl iodide (8.2 μl, 131 μmol) and sodium hydride (95%, 2.4 mg, 96 μmol) are subsequently added. The reaction solution is stirred at 0° C. for 2 h. After addition of a little water, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution for work-up. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness at 40° C. in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are freeze-dried, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-methoxymethylbenzonitrile (4 mg, 10.3 μmol) as a colourless solid. MS: 389.2 (M+H+), TLC (HPTLC): Rf=0.41 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[N:16]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([Cl:26])[S:23][C:13]=3[N:14]=2)[CH:18]=1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3cccnc3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18]2[S:19][C:20]([S:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]([OH:32])=O)[C:25]=3[F:33])=[CH:21][N:22]=2)=[N:15][CH:16]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:34][CH2:35][C:36]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([OH:40])[CH2:37][CH2:38][CH3:39].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[F:33][C:25]1[C:26]([C:30](=[O:32])[NH:34][CH2:35][C:36]([OH:40])([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:37][CH2:38][CH3:39])=[N:27][CH:28]=[CH:29][C:24]=1[S:23][C:20]1[S:19][C:18]([NH:17][C:14]2[N:15]=[CH:16][C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:12][CH:13]=2)=[N:22][CH:21]=1
Reactant: CCCC(O)(CN)c1ccccc1
Reactant: CN(Cc1ccc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)nc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(CN(C)C(=O)OC(C)(C)C)cn3)s2)c1F)c1ccccc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of 4-(2-(5-((tert-butoxycarbonyl(methyl)amino)methyl)pyridin-2-ylamino)thiazol-5-ylthio)-3-fluoropicolinic acid (120 mg, 0.244 mmol) and 1-amino-2-phenylpentan-2-ol (1.3 eq, 0.317 mmol, 57 mg) in NMP (4 mL) was added HOBT (1.3 eq, 0.317 mmol, 43 mg), EDAC (2 eq, 0.488 mmol, 94 mg) and diisopropylethylamine (5 eq, 1.22 mmol, 157 mg, 213 uL). The reaction was stirred at 23° C. overnight. The product was precipitated by addition of water to the reaction mixture. The solid was isolated by filtration to give the crude title material (97 mg, 61%) as a solid which was used as such in the next reaction. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.76 (3H, t, J=7.33 Hz), 0.90 (1H, m), 1.18-1.32 (1H, m), 1.41 (9H, s), 1.65-1.84 (2H, m), 2.75 (3H, s), 3.62 (2H, d, J=5.81 Hz), 4.32 (2H, s) 7.04 (1H, t, J=5.18 Hz), 7.11 (1H, d, J=8.59 Hz), 7.20 (1H, t, J=7.33 Hz), 7.31 (2H, t, J=7.71 Hz), 7.44 (2H, d, J=7.33 Hz), 7.66 (1H, s), 7.82 (1H, s), 8.13-8.32 (3H, m), 11.93 (1H, s). LC/MS (M+H)+: 653. Ret. time: 2.257 (Condition A).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH2:6][CH2:7][F:8])[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O1CCCC1.O>[C:4]([C:3]([NH:2][C:17](=[O:18])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:6][CH2:7][F:8])[CH3:9])#[N:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CCF
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C#N)(CCF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude rac-2-amino-4-fluoro-2-methylbutanonitrile hydrochloride product from Example 72A was initially charged in 165 ml of tetrahydrofuran/water (1:1), and 28.57 g (206.71 mmol) of potassium carbonate and 9.46 g (55.46 mmol) of benzyl chloroformate were added. The reaction mixture (biphasic mixture) was stirred at room temperature overnight. Another 1.72 g (10.1 mmol) of benzyl chloroformate were added to the reaction and the mixture was stirred at room temperature for a further 2 h. Subsequently, the biphasic system was separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with saturated aqueous sodium chloride solution, and then dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient=20/1 to 5/1). 5.04 g of the target compound were obtained (38% of theory over two stages, 96% purity).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:25][CH2:24][C:23](=O)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:25][CH2:24][C:23]3([O:4][CH2:1][CH2:2][O:3]3)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1
Reactant: OCCO
Reactant: O=C1CCN(c2nc(Cl)nc3c2CCC3c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Clc1nc2c(c(N3CCC4(C3)OCCO4)n1)CCC2c1ccccc1
Yield: 15.9 %

Procedure:
The mixture of ethylene glycol (46.9 μL, 0.841 mmol), 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one (Intermediate Gn) (132 mg, 0.421 mmol) and 4-methylbenzenesulfonic acid, H2O (8.00 mg, 0.042 mmol) in Benzene (1169 μL) was heated at reflux for 24 h in a Dean-stark apparatus. The resulting mixture was concentrated and purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100, 20 min) to get 7-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-dioxa-7-azaspiro[4.4]nonane (24 mg, 0.067 mmol, 15.94% yield). LC-MS (M+H)+=358.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.31 (2H, t, J=7.63 Hz), 7.20-7.25 (1H, m), 7.15 (2H, d, J=7.63 Hz), 4.21 (1H, dd, J=9.16, 6.10 Hz), 4.01-4.06 (4H, m), 3.89-3.97 (2H, m), 3.77-3.84 (2H, m), 3.26 (1H, ddd, J=15.03, 8.62, 5.95 Hz), 3.13 (1H, ddd, J=14.95, 8.85, 5.80 Hz), 2.53-2.63 (1H, m), 2.17 (2H, t, J=7.17 Hz), 2.03-2.12 (1H, m).
Reaction SMILES: [ClH:1].FC(F)(F)C1C=CC=CC=1O[C@H]1CCNC1.[OH:18][C@@H:19]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]1.[Br:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1O>>[ClH:1].[Br:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[O:18][C@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1ccc(F)cc1Br
Agent: Cl
Agent: FC(F)(F)c1ccccc1O[C@H]1CCNC1
Product: Fc1ccc(O[C@H]2CCNC2)c(Br)c1

Procedure:
The title compound was prepared in the same manner as described for (3S)-3-[2-(trifluoromethyl)phenoxy]pyrrolidine hydrochloride from tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate and 2-bromo-4-fluorophenol. 1H NMR (300 MHz, DMSO-d6): δ 7.62 (m, 1H), 7.32 (m, 1H), 7.13 (m, 1H), 5.31 (s, 1H), 3.60 (m, 1H), 3.32 (m, 3H), 2.12 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CS(C)=O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.016 mL cyclopropanemethanol in 10 mL dimethylsulfoxide was added 0.564 g sodium hydride 55% in mineral oil and the mixture was stirred at room temperature for 15 min. The resulting solution was added drop wise to a solution of 2.0 g 3,6-dichloropyridazine in 20 mL dry dimethylsulfoxide at room temperature and stirred at this temperature for 1 h. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 40:60 to yield 1.88 g of the title compound as white solid, MS 185.05 (M+H)+.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@H]2CCCN2)O)C=CC=CC=1.COB(OC)OC.B.C(N(CC)C1C=CC=CC=1)C.[O:39]=[C:40]([C:75]1[C:103]([F:104])=[CH:102][C:78]2[N:79]([CH2:94][O:95][CH2:96][CH2:97][Si:98]([CH3:101])([CH3:100])[CH3:99])[C:80]([C@@H:82]3[CH2:86][CH2:85][CH2:84][N:83]3[C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88])=[N:81][C:77]=2[CH:76]=1)[CH2:41][CH2:42][C:43]([C:45]1[C:73]([F:74])=[CH:72][C:48]2[N:49]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:50]([C@@H:52]3[CH2:56][CH2:55][CH2:54][N:53]3[C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])=[N:51][C:47]=2[CH:46]=1)=[O:44].CO.Cl>C1COCC1>[OH:44][C@H:43]([C:45]1[C:73]([F:74])=[CH:72][C:48]2[N:49]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:50]([C@@H:52]3[CH2:56][CH2:55][CH2:54][N:53]3[C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])=[N:51][C:47]=2[CH:46]=1)[CH2:42][CH2:41][C@@H:40]([C:75]1[C:103]([F:104])=[CH:102][C:78]2[N:79]([CH2:94][O:95][CH2:96][CH2:97][Si:98]([CH3:99])([CH3:100])[CH3:101])[C:80]([C@@H:82]3[CH2:86][CH2:85][CH2:84][N:83]3[C:87]([O:89][C:90]([CH3:91])([CH3:92])[CH3:93])=[O:88])=[N:81][C:77]=2[CH:76]=1)[OH:39]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C(=O)CCC(=O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)c1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc([C@@H](O)CC[C@H](O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Temperature: 0 °C
Yield: 92.9 %

Procedure:
To a solution of (R)-(+)-α,α-diphenyl-2-pyrrolidinemethanol (59.9 mg, 0.24 mmol) in THF (2.8 mL) was added trimethylborate (0.034 mL, 0.31 mmol), and the resultant solution was stirred for 90 minutes. The solution was cooled to 0° C. and N,N-diethylaniline borane (0.4 mL, 2.2 mmol) was added in portions over 30 minutes with stirring continued at 0° C. This solution was added via cannula to a 0° C. solution of di-tert-butyl (2S,2′S)-2,2′-[(1,4-dioxobutane-1,4-diyl)bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)]dipyrrolidine-1-carboxylate (265 mg, 0.28 mmol) in THF (2.8 mL) and then warmed to room temperature and stirred for 16 hours. The solution was cooled to 0° C. and CH3OH (0.09 mL, 2.2 mmol) was added, and the solution was warmed to room temperature and stirred for 2 hours. 1N HCl was added, and the aqueous solution was extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. Purification was run by flash chromatography (0-3% CH3OH/CH2Cl2) to give the title compound (248 mg, 0.26 mmol, 93%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:17]4[CH2:28][CH2:29][CH2:30][CH2:31][C:16]=4[CH:15]=[CH:14][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C(O)C>CCOCC>[O:27]=[C:19]1[C:18]2[C:17]3[CH2:28][CH2:29][CH2:30][CH2:31][C:16]=3[CH:15]=[CH:14][C:13]=2[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[NH:20]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)n2COCCOC)CCCC4)c1
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Yield: 53.1 %

Procedure:
Preparation of 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. HCl (4M in dioxane, 0.57 mL, 2.3 mmol) was added to a solution of 1-[2-(2-methoxy-ethoxymethyl)-1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol) and ethanol (0.57 mL). The reaction mixture was stirred at room temperature for 4 h, at which point ether (2 mL) was added and the precipitate was collected to yield the titled compound (27.0 mg, 49% yield). MS (ESI/Cl): mass calcd. for C18H18N4O3, 338.1; m/z found, 339.1 [M+H]+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.Cl[C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[CH:17][N:18]=2)[N:15]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>CS(C)=O>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:3][CH2:2]1
Reactant: NCC1CCSCC1
Reactant: FC(F)(F)Oc1cccc(-c2cnc3ccc(Cl)nn23)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)Oc1cccc(-c2cnc3ccc(NCC4CCSCC4)nn23)c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 5.6 %

Procedure:
To the solution of compound (tetrahydro-2H-thiopyran-4-yl)methanamine (150 mg, 1.14 mmol) and compound 6-chloro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazine (358 mg, 1.14 mmol) in 3 mL DMSO was added DIEA (0.22 mL, 2.28 mmol) and 10 mg CsF, the solvent was stirred for 5 h at 120° C., Then the mixture was purified by HPLC to afford the compound N-((tetrahydro-2H-thiopyran-4-yl)methyl)-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-amine (26 mg, 30%) as yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH2:23])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:39])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][CH:37]([CH3:39])[CH3:36])[N:15]([C:24]3[C:25]4[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][C:26]=4[N:27]=[CH:28][N:29]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CN)cccc43)c21
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1C(C(C)C)CC2
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
A stirring solution of (1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine (0.250 g, 0.43 mmol) in DCE (3 mL) was treated with acetone (0.159 mL, 2.17 mmol). The reaction was allowed to stir for 20 minutes, followed by the addition of NaBH(OAc)3 (0.184 g, 0.87 mmol). The reaction was stirred at room temperature overnight. An additional 2.5 equivalents of acetone and 1.0 equivalent of NaBH(OAc)3 were added to the reaction and stirred an additional 2 hours. The reaction was quenched by the addition of saturated NaHCO3 and diluted with DCM. The combined organics were washed with brine, dried Na2SO4, filtered, and concentrated under reduced pressure to give N-((1′-benzyl-1-(5-isopropyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (0.185 g, 84%), which was used without further purification. LCMS (APCI+) m/z 536.4 [M+H]+; Rt=3.61 min.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.S1(=O)(=O)CCCC1.[BH4-].[Na+]>>[CH:9]1[C:8]2[CH2:2][NH:3][C:4]3[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=3[S:6][C:7]=2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Suspend 3.035 gm. (10 mmole) of methyl 11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate in 30 ml. of solfolane (tetrahydrothiophene 1,1-dioxide) and add 766 mg. (20 mmole) of sodium borohydride in small portions with stirring. Stir at room temperature for 3 hours, add a further 190 mg. (5 mmole) of sodium borohydride and continue stirring for 1 hour. Pour the reaction mixture into 100 ml. of ice-water. Extract with three 50 ml. portions of dry ether. Wash the ether extract twice with 50 ml. portions of saturated aqueous sodium chloride, dry over magnesium sulfate and evaporate to a residue. Chromatograph the residue over 100 gm. of silica gel eluting with 1:9 ethyl acetate in toluene. Recrystallize the recovered product from acetonitrile to obtain the title product. (m.p. 149°-150° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:26][C:27]([F:42])([F:41])[C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:42][C:27]([F:26])([F:41])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:11])[CH2:6][CH2:5]4)[CH2:36][CH2:35]2)=[CH:32][CH:33]=1
Reactant: O=C1CCc2cc(O)ccc21
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C1CCc2cc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a stirred solution of 5-hydroxy-2,3-dihydro-1H-inden-1-one (0.74 g, 5.0 mmol) in toluene (30 mL) at room temperature was added diisopropyl azodicarboxylate (1.21 g, 6.0 mmol), 1-(4-trifluoromethylphenyl)piperidin-4-ol (1.47 g, 6.0 mmol), and triphenyl phosphine (1.57 g, 6.0 mmol). The mixture was stirred at 60° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford the title compound as a pale yellow solid (1.49 g, 79%). 1H-NMR (CDCl3, 300 MHz): δ 7.70 (m, 1H), 7.49 (m, 2H), 6.93 (m, 4H), 4.65 (m, 1H), 3.59 (m, 2H), 3.30 (m, 2H), 3.09 (m, 2H), 2.68 (m, 2H), 2.12 (m, 2H), 1.96 (m, 2H) ppm; MS (ESI): 376.6 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]3[C:20]=2[N:19]=[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=32)=[CH:8][CH:9]=1)=[O:4].[OH-].[K+].Cl>CO.O>[CH2:25]([CH:15]1[C:16]2=[C:17]3[CH2:24][CH2:23][CH2:22][CH2:21][C:18]3=[N:19][C:20]2=[C:12](/[CH:11]=[CH:10]/[C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH:13]=[CH:14]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC1C=CC(/C=C/c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCC1C=CC(/C=C/c2ccc(C(=O)O)o2)=C2N=C3CCCCC3=C21
Yield: 63.6 %

Procedure:
A solution of 6.5 g of (E)-5-[2-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo [b,d]pyrrol-6-yl)ethenyl]-2-furancarboxylic acid methyl ester from Example 33 in 72 ml of methanol was treated with a solution of 4.9 g of 87% potassium hydroxide in 18 ml of water. The mixture was refluxed for 45 minutes, cooled, diluted with water, acidified with 2N HCl and then extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6.0 g of crude acid. Crystallization from ethyl acetate and hexane afforded 4.0 g (63.7%) of (E)-5-[2-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)ethenyl]-2-furancarboxylic acid as yellow crystals, mp 142°-144° C.