Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=2[CH2:34][O:35]C(C2C=CC=CC=2)=O)[CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:23]=[C:24]([C:27](=[O:30])[CH2:28][CH3:29])[S:25][CH:26]=3)[CH:19]=[CH:20][CH:21]=2)=O)C=CC=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH:32][C:33]=1[CH2:34][OH:35])[CH2:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:23]=[C:24]([CH:27]([OH:30])[CH2:28][CH3:29])[S:25][CH:26]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: CCC(=O)c1cc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1cc(-c2cccc(OCc3ccc(CO)c(CO)c3)c2)cs1
Reaction time: 2 h

Procedure:
4.3 g (7.3 mmol) of 1-{4-[3-(3,4-bis(1-phenylmethanoyloxymethyl)benzyloxy)phenyl]-2-thiophenyl}-1-propanone are dissolved in 10 mL of THF and added dropwise to a suspension of 1.1 g (29 mmol) of lithium aluminium hydride, and the mixture is stirred for 2 hours. After treatment of the reaction medium with 1.1 mL of water, 1.1 mL of 15% sodium hydroxide and 3.3 mL of water, the medium is filtered. After purification by chromatography on silica gel (eluent: 3 heptane/7 ethyl acetate), the desired product is obtained in the form of a colourless oil (m=773 mg; Y=28%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21](=[O:23])[NH2:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:24])[CH:5]=1)([O-])=O>[Pt]=O.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21](=[O:23])[NH2:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:24])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(C(N)=O)cc2C1=O
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C(N)=O)cc2C1=O
Reaction time: 0.83 h

Procedure:
The mixture of 1.5 g of N-(4-nitro-o-tolyl)-4-carbamoylphthalimide 200 ml of ethyl acetate and 0.3 g of platinum oxide is hydrogenated at 2.5 atm. and about 40° for 50 minutes. It is filtered, the filtrate concentrated and the precipitate collected, to yield the N-(4-amino-o-tolyl)-4-carbamoylphthalimide melting at 240°-242°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl.N[C@@H]1CC[CH2:26][CH2:25][C@H:24]1[OH:29].O=O>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]2[CH2:24][O:29][CH2:26]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=O
Solvent: CC(C)O
Product: Brc1cccc(C2COC2)c1
Yield: 939.9 %

Procedure:
4.7 g of 3-bromophenylboronic acid, 219 mg of NiI2, 4.3 g of sodium bis(trimethylsilyl)amide, and 106 mg of trans-2-aminocyclohexanol hydrochloride were added to 14 ml of anhydrous 2-propanol and oxygen removed by passing argon through the mixture for 10 minutes. Then, a solution of 2.2 g of 3-iodo-oxetane in 1 ml of anhydrous 2-propanol was added and the mixture kept at 80° C. under microwave irradiation for 50 minutes. The mixture was then evaporated, distributed between 100 ml of water and 100 ml of EA, and the aqueous layer extracted twice using 20 ml of EA each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.4 g of the title compound, colorless oil. Rf (EA/HEP 1:4)=0.27
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:28]([N:30]3[CH2:35][CH2:34][CH2:33][CH:32]([OH:36])[CH2:31]3)=O)[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH2:2][O:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:28][C:24]2([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH2:27][CH2:26][CH2:25]2)[CH2:31]1
Reactant: O=C(N1CCCC(O)C1)C1(c2ccc(Cl)cc2)CCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)(F)c1cc(COC2CCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Following the procedure described in Example 72, 1-Bromomethyl-3,5-bis-trifluoromethyl-benzene was used to alkylate 56 mg (0.19 mmol) of [1-(4-Chloro-phenyl)-cyclobutyl]-(3-hydroxy-piperidin-1-yl)-methanone, forming the ether adduct [3-(3,5-Bis-trifluoromethyl-benzyloxy)-piperidin-1-yl]-[1-(4-chloro-phenyl)-cyclobutyl]-methanone (39 mg, 39%). A portion of this compound (22 mg, 0.043 mmol) was dissolved in 1 mL of THF and excess lithium aluminum hydride (16 mg, ca. 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 0.5 mL 1M NaOH. Additional THF (10 mL) was added, the suspension was stirred at room temperature for 30 minutes, and then was filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 3-(3,5-Bis-trifluoromethyl-benzyloxy)-1-[1-(4-chloro-phenyl)-cyclobutylmethyl]-piperidine, 189, was obtained (12 mg, 56%). Data for this compound: MS 506 (M++1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][O:38][C:37]([CH3:42])([CH3:41])[CH2:36]1>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][O:38][C:37]([CH3:41])([CH3:42])[CH2:36]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: CC1(C)CC(CCCBr)CCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 24.1 %

Procedure:
A mixture of N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate (149 mg, 0.425 mmol) and potassium carbonate (294 mg, 2.126 mmol) in DMF (2 ml) was stirred and heated at 60° C. under nitrogen for one hour. 4-(3-Bromopropyl)-2,2-dimethyltetrahydro-2H-pyran (125 mg, 0.532 mmol) in dry DMF (1 ml) was added and the mixture heated at 60° C. under nitrogen for a further 2.5 hours. The reaction mixture was cooled to room temperature, quenched into water (10 ml) and extracted with DCM:EtOAc (1:1, 2×20 ml). The organic extracts were combined, dried by passage through a hydrophobic frit and concentrated under vacuum. The residue was purified by mass directed autopreparation. Product containing fractions were combined and evaporated to give the title compound (40 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:10])[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[CH3:17][N:18]([CH3:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:17][N:18]([CH3:25])[CH:19]1[CH2:24][CH2:23][N:22]([C:7](=[O:9])[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:21][CH2:20]1
Reactant: O=C(O)C(=O)c1cccs1
Reactant: CN(C)C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
2-Thiopheneglyoxylic acid (300 mg, 1.9 mmol) was dissolved in 10 mL of methylene chloride. A 2.0 M solution of oxalyl chloride in methylene chloride (1.1 mL, 2.1 mmol) was then added, followed by 10 μL of DMF. The resulting solution was stirred at room temperature for 1 hour, then a solution of dimethylpiperidin-4-ylamine (271 mg, 2.1 mmol) and DIPEA (1.0 mL, 5.8 mmol) in 2 mL of methylene chloride was added. 4-Dimethylaminopyridine (12 mg, 96 μmol) was then added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then extracted with a saturated sodium bicarbonate solution, and the organic layer was dried over Na2SO4 and concentrated to yield the crude intermediate (4a) (498 mg), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32]>C1COCC1>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(N[C@@H](C)CO)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
To a THF (5 mL) solution of 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (615 mg, 1.5 mmol) was added (S)-2-amino-1-propanol (1.2 mL, 15 mmol) and stirred overnight at RT. Concentrated under vacuum and chromatographed on silica gel eluding with 2% methanol in dichloromethane and converted to the hydrochloride salt to give 295 mg 6-(2,4-difluoro-phenoxy)-2-((S)-2-hydroxy-1-methyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=407, MP=186.0-189.1° C.).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+]>O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][N:9]=1
Reactant: O=C(NCCc1ccccc1)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc(C2=NCCc3ccccc32)nc1
Temperature: 155 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of 14 g of pyridine-2-carboxylic acid phenethyl-amide and 300 g of polyphosphoric acid was stirred at 140° C. for 90 min., at 150° C. for 60 min. and finally at 155° C. for 60 min. The solution was cooled to 120° C. and poured into 2 l of water while stirring. The mixture was stirred at room temperature for a further 15 min. and made basic (strong warming|) by the addition of about 300 ml of 25% ammonium hydroxide while cooling with ice and stirring. Thereafter, the mixture was extracted with 2×400 ml of ethyl acetate. The combined raspberry-red organic phases were washed with 100 ml of 10% sodium chloride solution, dried over sodium sulfate, treated with about 5 g of Darco G60 and evaporated to dryness. There were obtained 11.6 g of 1-pyridin-2-yl-3,4-dihydro-isoquinoline as a yellowish oil, b.p. 130° C./0.08 mbar (bulb-tube).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:46])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]1[C:17]([C:37]2C(C)=CC(C)=CC=2C)=[N:18][N:19]2[C:24]3[NH:25][CH2:26][CH2:27][C:23]=3[C:22]([C:28]3C(C)=CC(C)=CC=3C)=[N:21][C:20]=12.[C:47](Cl)(=[O:51])[CH2:48][CH2:49][CH3:50].O>ClCCl>[C:10]1([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:46])[C:9]=1[C:16]1[C:17]([CH3:37])=[N:18][N:19]2[C:24]3[N:25]([C:47](=[O:51])[CH2:48][CH2:49][CH3:50])[CH2:26][CH2:27][C:23]=3[C:22]([CH3:28])=[N:21][C:20]=12
Reactant: CCCC(=O)Cl
Reactant: Cc1cc(C)c(-c2nc3c(-c4c(C)cc(C)cc4C)c(-c4c(C)cc(C)cc4C)nn3c3c2CCN3)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Reaction time: 2 h
Yield: 42.4 %

Procedure:
Triethylamine (0.091 mL, 0.652 mmol) was added to a solution of 3-mesityl-2,5-dimesityl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (100 mg, 0.326 mmol) which was prepared in Example 71 in dichloromethane (4 mL), butyryl chloride (0.037 mL, 0.358 mmol) was added dropwise at room temperature, followed by stirring for two hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, and then dried over MgSO4. The solvent was evaporated, and the residue was subjected to silica gel column cromatography (7 g), to give the title compound (52 mg, 42%) as a pale yellow oil from a fraction of ethyl acetate-hexane (1:4 v/v).
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:30]3[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Yield: 52 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (87 mg) was coupled to 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-ylamine as in General Procedure 4B to give the title compound as a light brown solid (52% yield). M.p.>200° C., LCMS: m/z=388.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.28 (2H, m), 3.51 (2H, m), 4.52 (2H, d, J=1.3 Hz), 6.58 (1H, dd, J=8.6, 0.8 Hz), 7.00 (1H, d, J=2.0 Hz), 7.05 (1H, m), 7.14 (1H, m), 7.30 (2H, s), 7.54 (1H, d, J=2.0 Hz), 7.58 (1H, dd, J=8.6, 2.5 Hz), 8.13 (1H, dd, J=2.4, 0.6 Hz).
Reaction SMILES: C([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:12]([CH3:26])([CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO>[CH:19]1([O:18][N:13]2[C:12]([CH3:25])([CH3:26])[CH2:11][CH:10]([OH:9])[CH2:15][C:14]2([CH3:17])[CH3:16])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1

Procedure:
The ester obtained in Example 2A is hydrolyzed using potassium hydroxide in aqueous methanol to give the title compound as a white solid melting at 74°-78° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:14])[C:5]2[C:10]([C:11](=[O:13])[CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:23]O>>[OH:14][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([O:13][CH3:23])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COC1=CC(=O)c2ccccc2C1=O
Reactant: CO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COc1cc(OC)c2ccccc2c1O
Reaction time: 1 h

Procedure:
A solution of 18.9 g of 2-methoxynaphthoquinone in methanol was added slowly to a solution of 34.8 g of sodium hydrosulfite in methanol and the mixture stirred for 1 hour. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to a purple solid. The solid was dissolved in 200 ml of methanol previously saturated with anhydrous hydrochloric acid and stirred for 3 minutes at 60° C. The mixture was then diluted with 200 ml of ice water and the precipitate filtered off, dried under vacuum and recrystallized from ether/pentane to give 13.25 g of 1-hydroxy-2,4-dimethoxynaphthalene, m.p. 87°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[C:21]3/[C:20](=[O:22])[NH:19][C:18](=[O:23])[S:17]/3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2ccc(Oc3ccc(F)cc3)cc2)S1

Procedure:
To a solution of 4-(4-fluorophenoxy)benzaldehyde (0.54 g, 2.5 mMol) and 2,4-thiazolidinedione (0.352 g, 3 mMol) in toluene (20 mL) were added piperidine (0.032 mL, 0.325 mMol) and benzoic acid (0.046 mg, 0.375 mMol). The reaction was refluxed for 4 h with continuous removal of water. The reaction was cooled and filtered. The crystalline product collected was washed with petroleum ether on the filter and dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17]([NH2:19])=[S:18].[ClH:20].[C:21](OCC)(=O)[CH3:22]>CN(C)C=O.O1CCOCC1.ICC>[ClH:20].[ClH:20].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH:16][C:17](=[NH:19])[S:18][CH2:21][CH3:22]
Reactant: CCOC(C)=O
Reactant: COc1ccnc(-c2ccc(F)c(NC(N)=S)c2)c1
Agent: Cl
Solvent: CCI
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCSC(=N)Nc1cc(-c2cc(OC)ccn2)ccc1F
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a suspension of N-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)-thiourea (0.1 g) in N,N-dimethylformamide (2 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.181 ml) and iodoethane (0.144 ml), and the mixture was stirred at 80° C. for 3 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 1 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(2-fluoro-5-(4-methoxypyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (125 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:14][C:15]([C:17]2([NH:32]C(=O)OC(C)(C)C)[CH2:22][CH2:21][N:20]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:11][O:12][CH3:13])=[CH:5][CH:4]=1>C(Cl)Cl.CO>[NH2:32][C:17]1([C:15]([NH:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11][O:12][CH3:13])=[O:16])[CH2:18][CH2:19][N:20]([C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:21][CH2:22]1
Reactant: COCCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCCC(NC(=O)C1(N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 48 h
Yield: 97.8 %

Procedure:
Hydrogen chloride (4M in 1,4-dioxane, 1.151 mL, 4.60 mmol) was added to tert-butyl 4-(1-(4-chlorophenyl)-3-methoxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (Intermediate 101) (50 mg, 0.09 mmol) in a mixture of DCM (5 mL) and methanol (2 mL) at 22° C. The resulting solution was stirred at 22° C. for 2 days. The mixture was evaporated and the residue was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M NH3/MeOH; pure fractions were evaporated to dryness and the residue was triturated with diethyl ether to afford 4-amino-N-(1-(4-chlorophenyl)-3-methoxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (39.0 mg, 96%) as a white solid.
Reaction SMILES: [NH3:1].[CH3:2][O:3][CH2:4][CH2:5][N:6]([CH2:16][CH2:17][O:18][CH3:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]=[C:14]=[S:15]>C(O)C>[CH3:19][O:18][CH2:17][CH2:16][N:6]([CH2:5][CH2:4][O:3][CH3:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:1])=[S:15]
Reactant: COCCN(CCOC)c1ccccc1N=C=S
Reactant: N
Solvent: CCO
Product: COCCN(CCOC)c1ccccc1NC(N)=S
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 10° C. The mixture was stirred at 0° C. for 8 hours and then stirred without cooling for 16 hours. The solvent was then removed by evaporation and the residue purified by chromatography on a silica column eluted with a 1:4 mixture of ethyl acetate and hexane and then a 1:1 mixture of ethyl acetate and hexane to give 1-((2-[bis(2-methoxyethyl)amino]phenyl)) thiourea (m.p. 118°-119° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:22])([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[NH2:50][C@H:51]([CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53]>CN(C=O)C.Cl>[CH3:22][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([CH2:13][O:14][Si:15]([CH3:17])([CH3:16])[C:18]([CH3:20])([CH3:21])[CH3:19])[C:10](=[O:12])[NH:50][C@@H:51]([C:52]([N:54]1[CH2:71][CH2:70][CH2:69][C:56]2([C:60](=[O:61])[N:59]([CH3:62])[CH2:58][CH:57]2[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH2:55]1)=[O:53])[CH2:72][O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@H](N)COCc3ccccc3)C2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(CO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)C2)C1=O
Reaction time: 0.25 h

Procedure:
A mixture comprising 2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)-2-methylpropanoic acid (intermediate from step 1) (311 mg, 0.934 mmol) and DIPEA (0.652 ml, 3.73 mmol) in DMF (5 mL) was treated with a solution of ®T3P (50% in EtOAc) (1.090 ml, 1.867 mmol) dropwise at room temperature. The resulting solution was stirred for 15 minutes, then 7-((R)-2-amino-3-(benzyloxy)propanoyl)-2-methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (intermediate from step 3) (500 mg, 0.934 mmol) in DMF (1 mL) was added dropwise at room temperature. The reaction mixture was stirred for 20 hours. The reaction mixture was diluted with 0.1M HCl (10 mL) and extracted with DCM (3×10 mL). The combined organic portions were washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), water (10 mL) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-70% EtOAc/iso-hexane afforded the title compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[S:20][CH:19]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C(O)(=O)C.O>[N:9]1([C:16]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[S:20][C:19]=2[Cl:1])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1csc(C2CCOCC2)c1)N1CCCCCC1
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cc(C2CCOCC2)sc1Cl)N1CCCCCC1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
N-Chlorosuccinimide (0.024 g, 0.18 mmol) was added to a solution of azepan-1-yl-[5-(tetrahydro-pyran-4-yl)-thiophen-3-yl]-methanone (53 mg) in acetic acid (2 mL). The reaction mixture was heated to 100° C. for 3 minutes using microwave irradiation, then diluted with water and purified by HPLC, eluting with 20%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (38 mg). LCMS m/z 328.17 [M+H]+ RT=10.59 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 6.6 (s, 1H), 4.05 (m, 2H), 3.7 (m, 2H), 3.5 (m, 2H), 3.4 (m, 2H), 2.9 (m, 1H), 1.9-1.5 (m, 12H).