Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[CH3:32][Mg]Br.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([CH3:32])([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(C)(O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O

Procedure:
A solution of 1.72 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 9.7 ml. of 3M methyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.26 g. of the title product as an oil, 80max film 3.00 (shoulder), 3.45, 5.80 (shoulder), 5.85, 6.45, 7.25, 10.30μ . NMR: δ1.32 (S, 15-methyl), 4.01 (S, 4, ketal), 4.40 (M, 2, CH2NO2), 5.22 (M, 2, 5 and 6-H), 5.63 (M, 2, 13 and 14-H) ppm. Mass spectrum: M+ at m/e 453), (theory 453), M+ --H2O at m/e 435.2571 (theory 435.2620).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:20])[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[Br:20][C:14]1[C:15]([O:17][CH2:18][CH3:19])=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH3:12])[C:9]=2[CH:13]=1
Reactant: CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1cc2c(cc1Br)C(C)CNCC2
Temperature: 20 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-ethoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.010 g, 0.026 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred overnight at 20° C. The product mixture was diluted with water (3 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (3 mL), dried with Na2SO4 and concentrated to give 0.007 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.63 (s, 1H), 4.07 (q, J=6 Hz, 2H), 3.03 (m, 3H), 2.91 (m, 3H), 2.73 (m, 1H), 2.26 (bs, 1H), 1.46 (t, J=6 Hz, 3H), 1.32 (d, J=7 Hz, 3H). MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.Cl[CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]>C(O)C>[N:25]1([C:23](=[O:24])[CH2:22][NH:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([NH:13][C:12]3[C:1]4[C:2]5[CH2:3][CH2:4][CH2:5][C:6]=5[S:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:15][CH2:16]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.[O:24]=[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:22][N:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([NH:13][C:12]2[C:1]3[C:2]4[CH2:3][CH2:4][CH2:5][C:6]=4[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)[CH2:15][CH2:16]1)[CH2:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Reactant: O=C(CCl)N1CCCC1
Solvent: CCO
Product: O=C(CN(CC(=O)N1CCCC1)[C@H]1CC[C@H](Nc2ncnc3sc4c(c23)CCC4)CC1)N1CCCC1
Product: O=C(CN[C@H]1CC[C@H](Nc2ncnc3sc4c(c23)CCC4)CC1)N1CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Note: For the preparation of the starting material compound 1, see Example 147. Into a 50-mL round-bottom flask, was placed 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (170 mg, 0.59 mmol, 1.00 equiv), 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (89 mg, 0.60 mmol, 1.00 equiv), KI (10 mg, 1.00 equiv) and ethanol (20 mL) at room temperature under nitrogen. The resulting solution was stirred overnight at 90° C. in an oil bath. The solvent was removed under reduced pressure. The crude product (180 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 50.0% in 21 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the desired trans-1-(pyrrolidin-1-yl)-2-[[4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino)cyclohexyl]amino]ethan-1-one (20.5 mg) as a white solid and trans-2-[[2-oxo-2-(pyrrolidin-1-yl)ethyl][4-([7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]amino)cyclohexyl]amino]-1-(pyrrolidin-1-yl)ethan-1-one (26.7 mg) as a white solid, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31](Cl)=[N:32][CH:33]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:29]=[N:30][C:31]([O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[N:32][CH:33]=1)=[O:27]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (m/e)=502.1 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[C:13]1([CH3:26])[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2([C:24]#N)[CH2:23][CH2:22][CH2:21][O:20]2)[CH:14]=1.[OH:27]S(O)(=O)=O>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:24]([C:19]1([C:15]2[CH:14]=[C:13]([CH3:26])[CH:18]=[CH:17][CH:16]=2)[CH2:23][CH2:22][CH2:21][O:20]1)=[O:27]
Reactant: Brc1ccccn1
Reactant: Cc1cccc(C2(C#N)CCCO2)c1
Reactant: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C2(C(=O)c3ccccn3)CCCO2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromopyridine (418 mg, 2.65 mmol) in THF (10 mL) was added n-BuLi (1.65 mL, 2.65 mmol, 1.6 N in hexane) at −78° C. After 15 mins, a solution of Example 91C (4.45 mg, 1.76 mmol) in THF (2 mL) was added. The mixture was stirred at −78° C. for 15 minutes and 2 mL of 1 M H2SO4 was added slowly. Then the mixture was heated at 50° C.-60° C. for 30 minutes. After cooling to room temperature, the aqueous phase was separated and extracted with ethyl acetate (15 mL×3). The combined organic phases was washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to provide the title compound. LC-MS: m/z (M+H): 268.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[NH:19][CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1.N1C=CC=C(C2N3C=CC(C(C4C5C(=CC([O:58][CH2:59]C6C=CC=CC=6)=CC=5)NC=4)=O)=C3CS2)C=1.[NH3:66]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:15]([C:17]4[C:25]5[C:20](=[CH:21][C:22]([C:26]6[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=6)=[CH:23][CH:24]=5)[N:19]([C:59](=[O:58])[NH2:66])[CH:18]=4)=[O:16])=[C:10]3[CH2:9][S:8]2)[CH:2]=1
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(OCc3ccccc3)ccc12
Reactant: N
Product: NC(=O)n1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21

Procedure:
The title compound was prepared by the procedure described in Example 37 using 3(-pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole, prepared as in Example 28, instead of 3-(Pyridin-3-yl)-7-(6-phenylmethoxyindol-3-yl)carbonyl-1H,3H-pyrrolo[1,2-c]thiazole. 1H NMR (DMSO-d6, 300 MHz) δ4.50 (d, 1H, J=15 Hz), 4.68 (dd, 1H, J=2, 15 Hz), 6.78 (d, 1H, J=3 Hz), 6.81 (s, 1H), 7.05 (d, 1H, J=3 Hz), 7.32 (t, 2H, J=9 Hz), 7.45 (dd, 1H, J=5, 8 Hz), 7.61 (dd, 1H, J=1, 9 Hz), 7.66-7.77 (m, 3H), 8.00 (bs, 2H), 8.30 (d, 1H, J=9 Hz), 8.53- 8.60 (m, 4H), MS (DCI/NH3) m/e 483 (M+H)+, 440. Anal calcd for C27H19FN4O2S: C, 67.21; H, 3.97; N, 11.61. Found: C, 66.92; H, 3.88; N, 11.44.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7])(C)(C)C.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br.[H-].[Na+]>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][N:13]([C:14]1[N:15]=[CH:16][C:17]([Br:20])=[CH:18][N:19]=1)[C@@H:11]1[CH2:12][N:8]([C:6]([OH:5])=[O:7])[C@H:9]([CH2:21][CH3:22])[CH2:10]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC[C@@H]1C[C@H](Nc2ncc(Br)cn2)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)CN1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (2R,4S)-4-(5-bromo-pyrimidin-2-ylamino)-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (13.0 mmol; 4.84 g), 3,5-bis(trifluoromethyl)benzyl bromide (26.0 mmol; 7.98 g) and sodium hydride (60% dispersion in mineral oil, 39.0 mmol; 1.56 g) in DMF (52 mL) is stirred for 1.5 hours at room temperature under nitrogen. The reaction mixture is quenched with water then saturated ammonium chloride solution. The product is extracted twice with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tent-butyl ester (5.57 g, 72%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[NH2:13][NH2:14]>>[NH:13]([C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[NH2:14]
Reactant: NN
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: O
Product: Cc1ccc(C(=O)O)c(NN)n1
Yield: 50 %

Procedure:
2-Chloro-6-methyl nicotinic acid (3.5 g, 0.02 m) was refluxed with hydrazine hydrate (5 ml) and absolute alcohol (20 ml) for 5 hours. The solid was separated, washed with alcohol and crystallised from water to yield 50% of 2-hydrazino-6-methylnicotinic acid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:22])=[O:21])[C:15]([O:17]CC)=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:12][CH2:13][C@@:14]([CH3:24])([S:20]([CH3:23])(=[O:21])=[O:22])[C:15]([OH:17])=[O:16])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(C2=CCCCC2)cn1)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@@](CCn1cc(C2=CCCCC2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of ethyl (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (370 mg, 1.04 mmol, 1.0 eq) in MeOH/THF (3 mL:3 mL) was added LiOH (52.5 mg, 2.19 mmol, 2.1 eq) in H2O (1.5 mL) and the mixture allowed to stir at RT overnight. The mixture was diluted with 5 mL of H2O and washed with Et2O. The aqueous layer was then acidified with 1 M HCl which precipitated out a white solid. The solid was filtered off and washed with heptane to give (2R)-4-[4-(cyclohex-1-en-1-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoic acid (339 mg, 99.5% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.66 (m, 1H), 7.41-7.35 (m, 1H), 6.05-5.96 (m, 1H), 4.78-4.59 (m, 1H), 4.55-4.38 (m, 1H), 3.14 (s, 3H), 2.77-2.64 (m, 1H), 2.51-2.37 (m, 1H), 2.28-2.19 (m, 2H), 2.18-2.06 (m, 2H), 1.80-1.69 (m, 2H), 1.64 (s, 5H). LC-MS M+H+327.1.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]([CH2:6][NH:7][C:8](=[O:16])[C:9]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=O)=[O:5].Cl.[NH2:18]O.Cl>CO.O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[N:18][OH:1])[C:8]([NH:7][CH2:6][C:4]([OH:3])=[O:5])=[O:16]
Reactant: NO
Reactant: O=C(O)CNC(=O)C(=O)c1cccs1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)C(=NO)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
17.6 g of powdered sodium hydroxide are added in portions to a mixture of 22 g of 2-thienylglyoxylic acid N-hydroxycarbonylmethyl-amide (prepared from aminoacetic acid and ethyl 2-thienylglyoxylate, melting point 168°-170° C.), 15 ml of water, 50 ml of methanol and 9.5 g of hydroxylamine hydrochloride. The temperature is maintained at 40°-50° C. by cooling and the mixture is then stirred at room temperature for 2 h. It is acidified with concentrated hydrochloric acid and then the volatile fractions are stripped off in a rotary evaporator. The residue is boiled with 300 ml of ethanol and filtered with active charcoal, and the filtrate is concentrated in vacuo. The residue is stirred with diethyl ether and filtered off with suction.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[S:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.NC1C(C(C2C(OC)=CC=C(F)C=2F)=S)=CN=C(NC2CCC(S(C[CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)(=O)=O)CC2)N=1.NC1C(C(C2C(OC)=CC=C(F)C=2F)=O)=CN=C(NC2CCC(S(CCCN3CCOCC3)(=O)=O)CC2)N=1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[S:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:61][CH2:62][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)(=[O:28])=[O:29])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N
Reactant: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCC(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N
Agent: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCC(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=S)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCOCC3)CC2)nc1N

Procedure:
By a similar procedure to the preparation of the compound of Example 1, {4-Amino-2-[4-(3-morpholin-4-yl-propane-1-sulfonyl)-cyclohexylamino]-pyrimidin-5-yl}(2,3-difluoro-6-methoxy-phenyl)-methanethione was made from {4-Amino-2-[4-(3-morpholin-4-yl-propane-1-sulfonyl)-cyclohexylamino]-pyrimidin-5-yl}(2,3-difluoro-6-methoxy-phenyl)-methanone (prepared in accordance with US 2004/0162303 A1, 60 mg). LC/MS (m+H)+: 570.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=O)[NH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:16])=O.N1C=CC=CC=1.O>C(#N)C>[Cl:16][C:5]1[O:6][C:2]([CH3:1])=[C:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(=O)[nH]c1-c1ccccc1
Solvent: c1ccncc1
Solvent: O
Solvent: CC#N
Product: Cc1oc(Cl)nc1-c1ccccc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a suspension of 5-methyl-4-phenyl-1,3-oxazol-2(3H)-one (430 mg, 2.45 mmol) in phosphorus oxychloride (2.36 g, 14.7 mmol) was added pyridine (194 mg, 2.45 mmol) and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was diluted with acetonitrile and added dropwise to water (about 30° C.). The organic materials were extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to give the title compound (233 mg, yield 49%) as a yellow oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[OH:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.O>ClCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[OH:23])[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncc(Br)c1
Reactant: O=Cc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccccc1CNc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
295 mg (1.4 mmol, 1.4 eq) of sodium triacetoxyborohydride are added to a solution of 173 mg (1 mmol, 1 eq) of 5-bromopyridin-3-ylamine (starting material 1) and 122 mg (1 mmol, 1 eq) of 2-hydroxybenzaldehyde (starting material 2) in 20 ml of dichloromethane. The solution is stirred at room temperature for 24 h. The medium is poured into water and stirred for 2 h. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, and then dried over sodium sulphate. The residue is chromatographed on silica gel (80/20 heptane/ethyl acetate). 2-[(5-Bromopyridin-3-ylamino)methyl]phenol is obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][N:13]3[C:19]=2[CH3:20])=[CH:4][CH:3]=1.[CH2:21]([N:23]=[C:24]=[S:25])[CH3:22]>C(O)C>[CH3:20][C:19]1[N:13]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]2=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24]([NH:23][CH2:21][CH3:22])=[S:25])=[CH:3][CH:4]=1
Reactant: Cc1ccn2c(C)c(CCc3ccc(N)cc3)nc2c1
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)Nc1ccc(CCc2nc3cc(C)ccn3c2C)cc1

Procedure:
A mixture of 2-[2-(4-aminophenyl)ethyl]-3,7-dimethylimidazo[1,2-a]pyridine (2.2 g) and ethyl isothiocyanate (0.8 ml) in ethanol (20 ml) was refluxed for 1.5 hours. The solvent was evaporated and the residue was triturated with diethyl ether. The precipitate was collected by filtration and dried to give 3,7-dimethyl-2-[2-{4-(3-ethylthioureido)phenyl}ethyl]imidazo[1,2-a]pyridine (2.42 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]([F:16])([F:15])[CH2:11][N:12]=[C:13]=[S:14]>C(#N)C>[F:9][C:10]([F:16])([F:15])[CH2:11][NH:12][C:13](=[S:14])[NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cncc(Cl)n1
Solvent: CC#N
Product: FC(F)(F)CNC(=S)Nc1cncc(Cl)n1
Reaction time: 8 h
Yield: 36.9 %

Procedure:
A solution of 2-amino-6-chloropyrazine (1 g.) in warm acetonitrile (15 ml.) was cooled to room temperature. Trifluoroethylisothiocyanate (1.6 g.) was added and the mixture stirred overnight. Further trifluoroethylisothiocyanate (1.6 g.) was added, and the mixture warmed gently on a steam bath for 2 hours, then heated under reflux for 2 hours. The mixture was allowed to cool and evaporated to dryness to yield a brown solid. This was washed with water, 2 N HCl solution, water again, and sucked dry. Recrystallisation from boiling toluene diluted with petroleum ether (b.p. 60°-80°) yielded colourless needles (0.77 g.) of 2-[3-(2,2,2-trifluoroethyl)thioureido]-6-chloropyrazine m.p. 170°-172°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][NH2:23])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(Cc1ccc(C(F)(F)F)cc1)c1ccc(F)cc1

Procedure:
5.1 g (18.1 mmol) of 4'-fluoro-2-(4-trifluoromethylphenyl)acetophenone was dissolved in 100 ml of ethanol, and 8.8 ml (181 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for 2 hours. After completion of the reaction, ethanol was distilled off under reduced pressure, and water was added to the residue. The mixture was extracted with dichloromethane. The extract was dried over an hydrous sodium sulfate, and the solvent was distilled off to obtain [4'-fluoro-2-(4-trifluoromethylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:31]=[C:30](N)[C:5]2[O:6][CH2:7][C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[CH:10]([C:11]([NH:13][C:14]3[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=3[CH:23]([CH3:25])[CH3:24])=[O:12])[C:4]=2[CH:3]=1.[C:33]([BH3-])#[N:34].[Na+].[CH3:37]C1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.Cl.C(O)C.C=O>CO>[Br:1][C:2]1[CH:31]=[C:30]([N:34]([CH3:33])[CH3:37])[C:5]2[O:6][CH2:7][C:8]3[CH:29]=[CH:28][CH:27]=[CH:26][C:9]=3[CH:10]([C:11]([NH:13][C:14]3[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=3[CH:23]([CH3:25])[CH3:24])=[O:12])[C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2c(N)cc(Br)cc21
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2c1cc(Br)cc2N(C)C

Procedure:
After 2.12 g of 2-bromo-6,11-dihydro-N-(2,6-diisopropylphenyl)-4-aminodibenz[b,e]oxepin-11-carboxamide (Compound 54) obtained in Example 88 was dissolved in 80 ml of methanol. 1.35 g of sodium cyanoborohydride and a small amount of Bromocresol Green were added to the solution, and 5.8M hydrochloric acid-ethanol solution were added to the solution under ice cooling to render the solution yellow. While 1.74 g of 37% formalin was added dropwise to the mixture at room temperature, 5.8M hydrochloric acid-ethanol solution was added to keep the reaction solution yellow. After the reaction was completed, the reaction solution was concentrated under reduced pressure and ethyl acetate and water were added to the residue. The mixture was made alkaline with 10N sodium hydroxide. The organic layer was washed with water and saturated sodium chloride aqueous solution successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate=5:1) to obtain 1.85 g of 2-bromo-6,11-dihydro-N-(2,6-diisopropylphenyl)-4-dimethylaminodibenz[b,e]oxepin-11-carboxamide.