Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:14]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[C:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)=[CH:13]2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: BrCC1CC1
Product: c1cnc2c(c1)c(C1CCNCC1)cn2CC1CC1

Procedure:
This compound was prepared following the procedure described in example 24, parts C and D, starting with 0.3 g (1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.175 g (1.23 mmol) of bromomethylcyclopropane. After standard work-up, 0.242 g (96% of yield) of the expected product were isolated.
Reaction SMILES: C(O[C:9](=[O:46])[CH2:10][CH2:11][CH:12]([N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[C:13]([N:15]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:16]C(OCC1C=CC=CC=1)=O)=[O:14])C1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>[Pd].O1CCCC1.CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][N:15]1[C:13](=[O:14])[CH:12]([N:35]2[C:36](=[O:45])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]2=[O:44])[CH2:11][CH2:10][C:9](=[O:46])[NH:16]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)CN(NC(=O)OCc1ccccc1)C(=O)C(CCC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1NC(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Reaction time: 16 h
Yield: 75 %

Procedure:
A suspension of 5-(N′-benzyloxycarbonyl-N-tert-butoxycarbonylmethyl-hydrazino)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-5-oxo-pentanoic acid benzyl ester (3) and 10% palladium on carbon (250 mg) in tetrahydrofuran (THF) (30 mL) and DMF (3 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was dissolved in 30 mL of dichloromethane. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (770 mg, 4 mmol) was added and the solution was stirred at room temperature for 3.5 hours. Solvent was removed in vacuo and the residue was dissolved in ethyl acetate (300 mL), then washed with water (100 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered, purified by flash chromatography using hexane/ethyl acetate (85/15 to 50/50) to afford 1.06 g (75% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 1.40 (s, 9H), 2.30-2.40 (m, 1H), 2.40-2.50 (m, 1H), 3.05-3.12 (m, 1H), 3.38-3.48 (m, 1 H), 3.90-4.00 (d, 1H), 4.60-4.70 (d, 1H), 5.55-5.63 (m, 1H), 7.65 (s, 1H), 7.75-7.7.9 (m, 2H), 7.88-7.92 (m, 2H). Analytical HPLC: 10.36 min. LC-MS (ES+): m/e=388 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17](=O)[NH:18]2)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([N:15]=[CH:16][C:17]([Cl:3])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1cnc2ccc(Br)cc2[nH]1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Clc1cnc2ccc(Br)cc2n1
Temperature: 80 °C
Reaction time: 17 h
Yield: 74.6 %

Procedure:
Thionyl chloride (407.5 mL; 5.59 mol), then N,N-dimethylformamide (34.6 mL; 0.45 mol) were added dropwise to a mixture of 7-bromo-2(1H)-quinoxalinone (500 g; 2.24 mol) in toluene (7.61 L). The reaction mixture was stirred at 80° C. for 17 hours then cooled to 35° C. and poured cautiously onto water. The bi-phasic mixture was stirred for 30 minutes and then decanted. The organic layer was evaporated to dryness and the residue crystallized in methyl-tert-butyl ether, filtered and the precipitate washed with methyl-tert-butyl ether and dried to give 407 g (74.7%) of 7-bromo-2-chloro-quinoxaline. Filtrate was evaporated and re-crystallized in methyl-tert-butyl ether to provide a second fraction of 72 g (13.2%) of 7-bromo-2-chloro-quinoxaline.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([N:16](COC)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:14][C:13]([Cl:33])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.O>Cl.O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([CH3:28])([CH3:27])[CH3:29])=[CH:24][CH:25]=3)(=[O:18])=[O:19])=[CH:14][C:13]([Cl:33])=[CH:12][N:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(N)n1)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2C(=O)c2cccc(N)n2)cc1
Temperature: 25 °C
Yield: 7.5 %

Procedure:
A mixture of N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (58.6 mg, 1.03 mmol) in 4 N HCl in dioxane (4 mL) and water (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, evaporated to dryness, and treated with saturated aqueous NaHCO3 solution until pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4), and concentrated in vacuo. The obtained residue was purified via column chromatography (SiO2, 70% EtOAc in hexanes) to afford N-[2-(6-amino-pyridine-2-carbonyl)-5-chloro-pyridin-3-yl]-4-tert-butyl-benzenesulfonamide (34.5 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ11.1 (s, 1H), 8.26 (d, 1H), 8.18 (d, 1H), 7.76 (d, 2H), 7.51 (t, 1H), 7.44 (d, 2H), 7.03 (d, 1H), 6.66 (d, 1H), 4.67 (s, 2H), 1.22 (s, 9H); ESMS m/z (relative intensity): 445.1 (M+H)+ (100).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClC(Cl)Cl>[CH3:25][S:26]([O:13][CH:10]1[CH2:11][CH2:12][CH:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])[CH2:8][CH2:9]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cc(F)ccc1OC1CCC(O)CC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC1CCC(Oc2ccc(F)cc2[N+](=O)[O-])CC1
Reaction time: 8 h

Procedure:
To a stirred mixture of 18.3 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol, 6.23 parts of pyridine and 135 parts of trichloromethane were added dropwise, during a 10 minutes period, 9 parts of methanesulfonyl chloride. Upon completion, stirring was continued overnight at room temperature. The whole was further stirred and refluxed for 2 hours. The reaction mixture was evaporated and the residue was stirred in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 8.5 parts of 4-(4-fluoro-2-nitrophenoxy)cyclohexanol methanesulfonate (ester); mp. 111.7° C. (intermediate 102).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][OH:7].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][C@@H:3]([O:8][CH3:9])[O:4][CH2:5][CH2:6][O:7][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CO[C@H](CO)OCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CO[C@H](COS(=O)(=O)c1ccc(C)cc1)OCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
1,5-dihydroxy-2(S)-methoxy-3-oxa-pentane (E4) (1.4 g, 10.3 mmole), prepared as described in Example 8, was dissolved in dry pyridine (10 ml) and treated at 0° C. with p-toluensulfonylchloride (6.4 g, 0.034 mole). The mixture was kept at 4° C. overnight, then was poured into an ice-water mixture and finally extracted with methylene chloride. The organic phase was washed with water, separated off, dried over anhydrous sodium sulphate, filtered off. The solvent was removed under reduced pressure. The crude material was chromatographed on a silicic acid column using methylene chloride as eluting agent to give 2.8 g (yield 62%) of pure title derivative,
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH3:8][C:9]1(C)[CH2:26][C:13]2=[C:14]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:27])[CH2:10]1>C1COCC1>[CH3:8][C:9]1([CH3:10])[CH2:26][C:13]2=[C:14]([C:19]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[O:20])[S:15][C:16]([S:17][CH3:18])=[C:12]2[C:11](=[O:27])[C:7]1=[CH:6][OH:5]
Reactant: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)CC(C)(C)C2
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1sc(C(=O)N2CCCC2)c2c1C(=O)C(=CO)C(C)(C)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a suspension of NaH (76 mg of a 60% dispension in oil, 1.9 mmol) in THF (5 ml,) was added ethyl formate (0.38 mL, 4.7 mmol) at 0° C. After stirring for 10 min a solution of 6,6-dimethyl-3-methylthio-1-(pyrrolidin-1-ylcarbonyl)-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (305 mg, 0.94 mmol) in THF (7 mL) was added. The cooling bath was removed and the mixture stirred at room temperature for 18 h. After this time MeOH (0.5 mL) followed by water (0.5 mL) were added and the mixture stirred for 10 min. The solvents were removed in vacuo and the residue dissolved in water. The mixture was acidified to pH1 using 1 M HCl and the resultant solid collected by filtration. The solid was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with EtOAc: DCM (10:90), to give the title compound (173 mg, 52%) as a pale yellow oil. 1H NMR (250 MHz, CDCl3) δ1.18 (6H, s),1.93-1.99 (4H, m), 2.63 (3H, s), 2.82 (2H, s), 3.56-3.70 (4H, m), 7.56 (1H, d, J=10.4 Hz), 14.63 (1H, d J=10.4 Hz).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1

Procedure:
According to the procedure example A12A, except substituting 3-iodo-1H-indazole-6-carbaldehyde and 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) δ ppm 10.11 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.83-3.78 (m, 4H), 3.01 (t, J=5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M+H]+, calcd for [C18H19N5O+H]+ 322.16.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][C:33]6[O:34][C:35]7[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=7[N:37]=6)([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Clc1nc2ccccc2o1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(Nc6nc7ccccc7o6)(CC4)CC5)n23)cc1
Temperature: 65 °C
Yield: 102.1 %

Procedure:
A pear shaped flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.20 g, 0.46 mmol, Example #7, Step B) and 2-chlorobenzo[d]oxazole (0.18 g, 1.1 mmol, TCI) in DMF (5.0 mL). To the suspension was added K2CO3 (0.16 g, 1.1 mmol) and the mixture was heated to about 65° C. for about 8.5 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved into EtOAc (25 mL) and washed with water and brine (25 mL each). The organic solution was dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzo[d]oxazol-2-amine (0.26 g, 95%, 95% purity by ELSD): LC/MS (Table 2, Method d) Rt=1.48 min; MS m/z: 554 (M+H)+.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 15 g of product from Example 2, 160 ml methylene chloride and 5 drops dimethylformamide is added 5.87 ml oxalyl chloride. The reaction mixture is stirred at room temperature for 18 hours, concentrated in vacuo, dissolved in 300 ml of diethyl ether, filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 15.5 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(OCC)(=O)C>[C:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: OCc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(CO)cc1
Reaction time: 18 h
Yield: 28.3 %

Procedure:
To a solution of 4-hydroxybenzyl alcohol (7.5 g, 60 mmol) and 8.4 mL of triethylamine (8.4 mL, 60 mmol) in 100 mL of ethyl acetate, cooled in an ice bath, was added, via canula over 15 min, a solution of acetyl chloride (4.7 mL, 66 mmol) in 50 mL of ethyl acetate. The mixture was stirred in the same bath, which was left to come to room temperature on its own. After 18 h, the precipitate was removed by filtration. It was rinsed with 50 mL of ethyl acetate in small portions. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel, using 3:2 hexanes:ethyl acetate as the eluent, to afford 60 (2.853 g, 17 mmol, 29%) as an oil. 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 4.69 (d, J=5.8 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=O)[C:11]1([CH3:17])[CH3:16]>C(O)C.O>[OH:9][C:10]1([CH3:18])[CH2:14][CH2:13][C:12](=[N:7][OH:8])[C:11]1([CH3:17])[CH3:16]
Reactant: CC1(O)CCC(=O)C1(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(O)CCC(=NO)C1(C)C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
Sodium acetate (7.57 g, 92 mmol) and hydroxylamine hydrochloride (6.01 g, 87 mmol) were added to a solution of 3-hydroxy-2,2,3-trimethylcyclopentanone (8.20 g, 57.7 mmol, from Step 1) in ethanol (80 mL) and water (16 mL). The resultant mixture was heated to 80° C. for 15 h, then cooled to room temperature. After removal of ethanol in vacuo, the aqueous residue was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (30 mL), dried (MgSO4), filtered and concentrated to give crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g). 1H NMR (400 MHz, methanol-d4) δ ppm 2.29-2.80 (2 H, m), 1.63-1.94 (2 H, m), 1.22 (3 H, s), 1.08 (3 H, s), 0.99 (3 H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-:47][Cr](O[Cr]([O-])(=O)=O)(=O)=O>CN(C=O)C>[C:29]([O:28][C:27]([N:26]([CH3:34])[CH:23]1[CH2:22][CH2:21][CH:20]([O:19][C:10]2[C:9]3[C:8]4[C@@H:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([OH:47])=[O:1])[CH2:18][CH2:17][C:16]=4[S:15][C:14]=3[N:13]=[CH:12][N:11]=2)[CH2:25][CH2:24]1)=[O:33])([CH3:31])([CH3:30])[CH3:32]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCCO)CC4)CC1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](COCCC(=O)O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 50.1 %

Procedure:
A 50-mL round-bottom flask was charged with a solution of tert-butyl N-(4-[[(3S)-3-[(3-hydroxypropoxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (370 mg, 0.75 mmol, 1.00 equiv) in 5 mL of DMF and PDC (1.656 g, 4.40 mmol, 5.85 equiv) was added at room temperature. The resulting solution was stirred for 14 hrs at 25° C. After completion, the resulting solution was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2) to give 3-[[(3S)-12-[(4-[[(tert-butoxy)carbonyl](methyl)amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methoxy]propanoic acid (190 mg, 50%) as a colorless oil. MS: m/z 492 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH3:13][Sn:14](Cl)([CH3:16])[CH3:15].O>C1COCC1>[CH3:13][Sn:14]([CH3:16])([CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Brc1ccccn1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C[Sn](C)(C)c1ccccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere, 7.5 ml of n-butyllithium (15% strength in hexane, 12 mmol) were added dropwise to a solution of 1.9 g (12.0 mmol) of 2-bromopyridine in 50 ml of absolute THF cooled to −78° C. After stirring at −78° C. for 1 h, 12 ml (12 mmol) of a 1 M solution of trimethyltin chloride in THF were added dropwise and the mixture was stirred at −78° C. for a further hour. The reaction solution was warmed to 0° C. and treated with water. The organic phase was separated off and the aqueous phase was extracted a number of times with diethyl ether. The combined organic phases were dried over sodium sulfate and concentrated. The residue was distilled in vacuo (0.3 bar) in a bulb tube. 1.9 g of the title compound resulted as a colorless oil.
Reaction SMILES: [N:1]1([C:8]2[C:9]3[S:25][CH:24]=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[F:22])[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](=[O:28])=[O:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[N:1]1([C:8]2[C:9]3[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([Cl:21])=[CH:16][C:15]=3[F:22])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Reactant: O=C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1cc2nc(-c3cc(F)c(Cl)cc3F)nc(N3CCCCCC3)c2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14181.2 %

Procedure:
3.32 ml of 1.59M n-butyllithium-hexane solution was added dropwise for 5 minutes at −78° C. into a mixture of 1.82 g of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine and 40 ml of THF and stirred for 15 minutes. Approximately 50 g of crushed dry ice was added to the reaction mixture and the temperature subsequently raised to room temperature. 50 ml of 10% citric acid solution was added to the reaction mixture and extracted with EtOAc. After the organic layer washed with a saturated saline solution and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a foam-like substance. The foam-like substance was recrystallized from THF-acetonitrile to give 288 g of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:14]>C(#N)C>[C:1]1(/[CH:7]=[CH:8]/[S:9]([NH2:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
3.3 g (1 mol equiv.) Trans-2-phenyl-ethenesulfonyl chloride was dissolved in 33 mL acetonitrile and cooled to 0° C. Dropwise, 7.7 mL (3 eq) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 1.13 g (38%) trans-2-phenyl-ethenesulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (br.s., 2H), 7.23 (d, J=16.0 Hz, 1H), 7.31 (d, J=16.0 Hz, 1H), 7.41-7.45 (m, 3H), 7.64-7.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:19]([NH2:20])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:21][N:22]=[C:23]=[S:24]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:19]([NH:20][C:23]([NH:22][CH3:21])=[S:24])=[N:18][C:12]2[N:13]=[C:14]([CH3:17])[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CN=C=S
Solvent: Cc1ccccc1
Product: CNC(=S)Nc1nc2nc(C)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
A mixture of 25.0 g of 6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]pyrimidin-7-amine and 18.0 g of methyl isothiocyanate in 125 ml of toluene is heated at reflux for 28 hours. Cooling gives a precipitate of crude product which is collected by filtration and washed with ether. Further purification may be effected by recrystallization from isopropanol to give N-[6-(2,6-dichlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-yl]-N'-methylthiourea, mp 207.5°-208.5° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccc(N)cc2)CCCCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-cyclohexanecarbonitrile (0.500 g, 2.17 mmol, as prepared in the previous step) in EtOH (6 mL) and water (6 mL) was treated with NH4Cl (1.16 g, 21.7 mmol) and Fe powder (606 mg, 10.9 mmol) and heated to 50° C. for 2 h. The cooled mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was partitioned between water (50 mL) and EtOAc (75 mL), and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (488 mg, 100%) as an orange oil. The compound was used in the following step without purification. Mass spectrum (ESI, m/z): Calcd. for C13H16N2, 201.1 (M+H), found 201.3.