Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15]([CH3:16])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc2c(cc1SC)CCN(C(C)=O)CC2
Product: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2

Procedure:
Following the general procedure of Example 4 Method B, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:9]([OH:22])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=1>ClCCl>[CH2:1]([C@H:8]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:9]([OH:22])[CH:10]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1([CH3:21])[O:20][CH2:19][CH2:18][O:17]1)[S:48]([C:45]1[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=1)(=[O:50])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCCCCC1(C)OCCO1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)C(NCCCCC2(C)OCCO2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1

Procedure:
To a solution of the product of Step 2 (0.63 g, 1.49 mmol) in anhydrous dichloromethane (7 mL) at 0° C. was added N-ethyldiisopropylamine (0.38 g, 0.51 mL, 2.98 mmol) and a solution of 4-methoxybenzenesulfonyl chloride (0.32 g, 1.56 mmol) in anhydrous dichloromethane (2 mL) and the mixture was stirred at ambient temperature under nitrogen atmosphere for 18 hours. The mixture was washed sequentially with 1M hydrochloric acid, sodium bicarbonate/water, brine, dried (sodium sulfate) and concentrated. The residue was chromatographed (silica gel, dichloromethane/methanol, 97:3) to provide the title compound as a thick oil.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[N:15]O)O.[H][H].C[OH:20]>[Pt]=O>[NH2:15][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:20])=[O:1]
Reactant: CO
Reactant: [H][H]
Reactant: O=CCCCCCCCCCCC(O)=NO
Agent: O=[Pt]
Product: NCCCCCCCCCCCC(=O)O
Yield: 92 %

Procedure:
In a paar hydrogenation bottle was placed 0.92 g (4×10-3 mol) 12-oxododecanoic acid oxime, 10 mL methanol, and then 0.005 g (2.2×10-5 mol) platinum oxide (Adam's catalyst). The bottle was fitted to a paar high-pressure system, deaerated, then filled with hydrogen gas to maintain a pressure of about 3 atm for 1.5 hours with continuous shaking. After hydrogenation, 10 mL of methanol was added to the reaction mixture, then heated to gentle boiling to dissolve the product. The hot mixture was quickly filtered to remove suspension of black platinum, after which the filtrate on evaporation gave 0.85 g (92% yield) 12-aminododecanoic acid. Recrystallization was effected with ethanol/water mixture (1:1) to give 0.80 g (87% yield) 12-aminododecanoic acid (m.p. 184°-186° C, Lit. 185°-187° C.).
Reaction SMILES: [N+]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)([O-])=O.[C-:15]#[N:16].[K+].CS(C)=[O:20]>>[C:15]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:4]=1[OH:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:16]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CS(C)=O
Reactant: [C-]#N
Agent: [K+]
Product: CCOC(=O)c1ccc(O)c(C#N)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Ethyl 4-nitrobenzoate (50.0 g, 256 mmol) and potassium cyanide (51.2 g, 786 mmol) were added to DMSO (380 mL), stirred at 100° C. for 4 hours, and cooled to room temperature. DMSO was distilled off, and to the residue was added ice-water (200 mL). The aqueous residue was washed with ethyl acetate (100 mL). To the mixture was added conc. hydrochloric acid, to change the pH of the mixture to 1. The mixture was then extracted with ethyl acetate (200 mL), washed with aqueous saturated brine (50 mL), dried over anhydrous sodium sulfate, and placed under reduced pressure to distill the solvent off. There was obtained 51.4 g of ethyl 3-cyano-4-hydroxybenzoate as a crude product.
Reaction SMILES: [C:1](=[O:28])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH:29]1[CH:30]=[CH:31][C:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:33][CH:34]=1.CCN(CC)CC>CN(C=O)C>[C:32]1([N:35]2[CH2:40][CH2:39][N:38]([C:1]([O:2][CH2:3][CH2:4][N:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:9][CH2:10]3)=[O:28])[CH2:37][CH2:36]2)[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)N2CCN(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
2-(4-(tert-Butoxycarbonyl)piperazin-1-yl)ethyl 4-nitrophenyl carbonate (7.01 g, 17.7 mmol) was dissolved in DMF (150 mL). Phenylpiperazine (2.8 mL, 18.3 mmol) and NEt3 (3.0 mL, 21.5 mmol) were added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (250 mL), washed with 1M aq Na2CO3 solution (5×250 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, 0-100%) to give 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl 4-phenyl-piperazine-1-carboxylate (5.68 g, 77%) as a yellow oil. 2-(4-(tert-Butoxycarbonyl)-piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate (0.45 g, 1.07 mmol) was dissolved in a mixture of DCM (30 mL) and 2M HCl in Et2O (4 mL, 8 mmol) and stirred overnight. The supernatant was discarded. The residue washed with DCM (3×15 mL) and dried in vacuo to give 2-(piperazin-1-yl)ethyl 4-phenylpiperazine-1-carboxylate trihydrochloride (0.42 g, 98%) as a pale brown glass.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 3:1) to yield 80 mg (31%) colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][C:10]([C:12]2[CH:16]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:14][C:13]=2[Cl:24])=[O:11])=[CH:4][CH:3]=1.C(OC(OCC)OCC)C.[C:38]([O:41][C:42](=O)[CH3:43])(=O)[CH3:39].[NH2:45][CH2:46][CH2:47][N:48]1CCOC[CH2:49]1>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8](=[O:25])[C:9]([C:10]([C:12]2[CH:16]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:14][C:13]=2[Cl:24])=[O:11])=[CH:49][NH:48][CH2:47][CH2:46][N:45]2[CH2:43][CH2:42][O:41][CH2:38][CH2:39]2)=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(CC(=O)c1cc(CN2CCOCC2)sc1Cl)NCc1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1)C(=CNCCN1CCOCC1)C(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of N-(4-chlorobenzyl)-3-(2-chloro-5-(morpholin-4-ylmethyl)thien-3-yl)-3-oxopropanamide (Preparation 20, 20.0 g), triethylorthoformate (15.4 mL), and acetic anhydride (15.4 mL) is heated to 150° C. with removal of the distillate with a Dean-Stark trap. After 3 h, the volatiles are removed at 40 Torr (50° C.) and then at 0.2 Torr (100° C.) for 1 h to afford a brown oil. A portion of this residue (10.0 g) is dissolved in ethanol (150 mL) and N-aminoethylmorpholine (4.1 g) is added. The mixture is stirred at room temperature for 24 h and then is concentrated in vacuo. The crude product is purified by column chromatography (CH2Cl2/methanol, 97/3) to afford 4.28 g of the title compound as a brown oil. Physical characteristics. 1H NMR (300 MHz, DMSO-d6) δ 10.51, 9.89, 7.62, 7.58, 7.37, 6.92, 4.44, 3.62, 3.58, 3.47, 3.40, 2.42, 2.32.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21][CH3:22])=[O:20].Cl.[H][H].[CH3:26][N:27]1[CH:31]=[C:30]([NH:32][C:33]([C:35]2[N:36]([CH3:43])[CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=2)=[O:34])[CH:29]=[C:28]1[C:44]([OH:46])=O.C(Cl)CCl.CCN(C(C)C)C(C)C>[Pd].CC(N(C)C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([NH:15][C:44]([C:28]3[N:27]([CH3:26])[CH:31]=[C:30]([NH:32][C:33]([C:35]4[N:36]([CH3:43])[CH:37]=[C:38]([N+:40]([O-:42])=[O:41])[CH:39]=4)=[O:34])[CH:29]=3)=[O:46])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: [H][H]
Reactant: COC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Reactant: Cn1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cc1C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(NC(=O)c2cc(NC(=O)c3cc(NC(=O)c4cc([N+](=O)[O-])cn4C)cn3C)cn2C)cn1C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
In a hydrogenation bottle was added methyl 1-methyl-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxylate (2.0 g, 6.53 mmol), 80 ml of DMA, 500 mg of 10% Pd/C (50% wet) and 0.4 ml of HCl (conc.). After evacuation under vacuum, the bottle was placed under 50 psi hydrogen and shaken for 4 hours. The mixture was filtered through celite, evaporated to dryness without further purification. To the dry mixture was added 1-methyl-4-(1-methyl-4-nitro-1H-pyrrole-2-carboxamido)-1H-pyrrole-2-carboxylic acid (1.49 g, 5.10 mmol), 30 ml of DMA, EDC (4.0 g, 20.8 mmol) and DIPEA (1.0 ml, 5.75 mmol). The mixture was stirred under Ar overnight, concentrated, diluted with Hexane/EtAc (1:1, 10 ml) and water 10 ml to form precipitates. The precipitates were filtered, washed 1M NaH2PO4, 1 M NaHCO3 and water, dried over P2O5 under vacuum to afford 2.13 g (76%) of the title product. 1H NMR (DMSO) 10.28 (s, 1H), 10.25 (s, 1H), 9.78 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.31 (d, 1H, J=1.7 Hz), 7.25 (s, 1H), 7.23 (s, 1H), 7.17 (d, 1H, J=1.5 Hz), 6.98 (s, 1H), 6.71 (s, 1H), 4.02 (s, 3H), 3.94 (s, 3H), 3.83 (s, 3H), 3.73 (s, 3H), 3.56 (s, 3H), 1.47 (s, 9H); 13C NMR 160.78, 158.93, 158.06, 157.81, 135.25, 127.28, 126.36, 123.78, 122.57, 121.91, 121.40, 120.94, 119.65, 110.73, 108.39, 107.34, 103.75, 80.81, 51.57, 39.74, 38.52, 38.22, 37.08, 28.63; MS m/z+ 573.2 (M+Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.[Li][C:15]([CH3:18])([CH3:17])[CH3:16].[CH3:19][CH2:20][O:21]CC>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:20](=[O:21])[CH3:19])[CH:10]=2)[C:5]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH2:3]1
Reactant: [Li]C(C)(C)C
Reactant: CCOCC
Reactant: CC1(C)CCC(=O)c2ccccc21
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(2-methyl-1,3-dioxolan-2-yl)]-3,4-dihydro-4,4-dimethylnaphthlen-1(2H)-one ((Compound D15, 353 mg, 1.36 mmol) in 3 ml of dry ether at -78° C. was added dropwise t-BuLi (1 ml, 1.7 mmol, 1.7M solution in pentane). This clear light yellow solution was left at -78° C. for 30 min. Then, freshly distilled SOC12 (0.15 ml, 2.0 mmol) was added. The reaction mixture was stirred at -78° C. for additional 30 min and thereafter slowly warmed to room temperature. The reaction was quenched by addition of saturated NH4Cl. The white solids were removed by filtration and the clear solution was concentrated to an oil, and purified by column chromatography with ethyl acetate/hexane (1/10) to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28](C(OC(C)(C)C)=O)[CH:29]=[N:30][C:23]=12.C(N(C(C)C)CC)(C)C.C(O)CCC>CC1C(NC(CN2CCOCC2)=O)=C(C)C=C(OCC2C=CC=CC=2)C=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:22]1[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[N:30][C:23]=13)=[CH:7]2
Reactant: CC(C)(C)OC(=O)n1cnc2c(Cl)ccnc21
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: Cc1cc(OCc2ccccc2)cc(C)c1NC(=O)CN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1ccccc1-c1nc2c(Cl)cccc2cc1CNc1ccnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
A sealed flask was charged with (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)-methanamine, made in procedure E in A-1216 US PSP, tert-butyl 7-chloro-3H-imidazo[4,5-b]pyridine-3-carboxylate (109 mg, 429 μmol), diisopropylethylamine (0.075 mL, 429 μmol) and 1-butanol (2.0 mL, 21856 μmol). The mixture was subjected to microwave at 180° C. for 120 min. After cooled to room temperature, the mixture was concentrated, and the residue was diluted with MeOH. The solution was purified by HPLC, 25%-45% of B in 35 min. The collected fractions were dissolved in CH2Cl2 and neutralized by washing with aq. NaHCO3, the CH2Cl2 layer was dried, concentrated and gave N-((8-chloro-2-(2-chlorophenyl)-quinolin-3-yl)methyl)-3H-imidazo[4,5-b]pyridin-7-amine (20.2 mg, 15%), 1H NMR (DMSO-d6) δ ppm 12.72 (1H, s), 8.43 (1H, s), 8.15 (1H, s), 8.09 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=8.0 Hz), 7.73-7.80 (2H, m), 7.63-7.70 (4H, m), 7.45 (1H, s), 6.13 (1H, d, J=8.0 Hz), 4.60 (2H, br). Mass Spectrum (ESI) m/e=420.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10].[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[CH:5][N:4]=[C:3]1[N+:9]([O-:11])=[O:10]
Reactant: Cn1c(C=O)cnc1[N+](=O)[O-]
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cn1c(CO)cnc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.55 g. of 1-methyl-2-nitro-5-imidazolecarboxaldehyde in 200 ml. of ethanol, a solution of 1.9 g. of NaBH4 in 150 ml. of ethanol is added at about -4° C. After stirring for 15 minutes at 0° C., the excess of NaBH4 is decomposed with 10% hydrochloric acid and the reaction mixture is filtered. The residue, which is obtained by evaporation of the filtrate, is crystallized from acetone and yield 1 g. of the title product which melts at 142°-144° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([Cl:39])=[CH:24][N:23]=1.Cl.O1CCOCC1>CC(O)C>[Cl:39][C:25]1[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[N:27][C:22]([NH:1][C:2]2[CH:3]=[C:4]3[C:10](=[CH:11][CH:12]=2)[CH:9]2[CH2:13][CH2:14][CH:5]3[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:8]2)=[N:23][CH:24]=1
Reactant: Nc1ccc2c(c1)C1CCC2CN(C(=O)C(F)(F)F)C1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Temperature: 120 °C
Yield: 77.9 %

Procedure:
1-(4-Amino-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (30 mg, 0.106 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (34.5 mg, 0.116 mmol, 1.1 eq) were dissolved in IPA (1.5 mL). 4.0 M HCl in dioxane (29 μL, 0.116 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 20 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (10 mL) and washed with sat. NaHCO3 (10 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-75% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a yellow foam (45 mg, 78%). LCMS (m/e) 545 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.01 (s, 1H), 8.61 (d, 1H, J=8.4 Hz), 8.10 (s, 1H), 7.53-7.40 (m, 3H), 7.36-7.26 (m, 1H), 7.13-6.95 (m, 3H), 6.22 (bs, 1H), 4.31-4.17 (m, 1H), 3.92-3.82 (m, 1H), 3.40-3.28 (m, 1H), 3.22-3.08 (m, 2H), 3.04 (d, 3H, J=4.5 Hz), 2.10-1.98 (m, 2H), 1.88-1.72 (m, 2H), 1.30-1.20 (m, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13].BrBr>C(O)(=O)C>[CH3:1][C:2]1[C:3]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:4][NH:5][C:6](=[O:8])[CH:7]=1
Reactant: CC1CC(=O)NN=C1c1cccc(C#N)c1
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1cccc(C#N)c1

Procedure:
A 15 g. portion of m-(1,4,5,6,-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal of Medicinal Chemistry 17, 281 (1974)]is suspended in 75 ml. of glacial acetic acid with stirring at steam bath temperature. Then 3.75 ml. of bromine in 25 ml. of acetic acid is added dropwise over a 15 minute period. The reaction mixture is heated on a steam bath for an additional a30 minutes then is poured onto crushed ice. The resulting solid is collected by filtration, copiously washed with water and dried to afford m-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a cream colored solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:30][N:31]([CH3:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1>>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=3[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:35][CH:34]=1)[CH3:48]
Reactant: CN(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)nn2C(C)C
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN(C)C)cc2)cc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 67 from 6-bromo-3-methyl-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (0.090 g, 0.196 mmol) and N,N-dimethyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (0.070 g, 0.235 mmol). The product was collected as a white solid (72 mg, 70%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.33 Hz, 3H), 1.45 (d, J=6.57 Hz, 6H), 1.56 (sxt, J=7.53 Hz, 2H), 2.07-2.23 (m, 9H), 2.44 (s, 3H), 2.52-2.59 (m, 2H), 3.43 (s, 2H), 4.38 (d, J=5.05 Hz, 2H), 5.06 (quin J=6.63 Hz, 1H), 5.90 (s, 1H), 7.33-7.45 (m, 3H), 7.75 (d, J=8.08 Hz, 2H), 7.93 (d, J=1.26 Hz, 1H), 8.45 (t, J=4.93 Hz, 1H), 11.50 (s, 1H); LCMS (ES+) m/z: 514.5.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])(=O)=O)=CC=1.[OH:22][C:23]1[CH:32]=[CH:31][C:26]2[CH:27]([CH3:30])[CH2:28][O:29][C:25]=2[CH:24]=1>>[CH3:20][CH:13]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH2:12][CH2:11][O:22][C:23]1[CH:32]=[CH:31][C:26]2[CH:27]([CH3:30])[CH2:28][O:29][C:25]=2[CH:24]=1
Reactant: CC(C)=CCCC(C)CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC1COc2cc(O)ccc21
Product: CC(C)=CCCC(C)CCOc1ccc2c(c1)OCC2C

Procedure:
3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-2,3-dihydrobenzofuran of boiling point 126°-128° C./0.001 mmHg; nD20 = 1.5223; and 3,7-dimethyl-6-octenyl p-toluenesulfonate and 6-hydroxy-3-methyl-2,3-dihydrobenzofuran are reacted to produce 6-[(3,7-dimethyl-6-octenyl)-oxy]-3-methyl-2,3-dihydrobenzofuran of boiling point (bulb-tube) 130° C./0.14 mmHg; nD20 = 1.5150.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([OH:12])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[NH:46][CH2:45][CH2:44][CH2:43]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([N:46]2[C:47]3[C:42](=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:37])[CH2:43][CH2:44][CH2:45]2)=[O:12])=[N:6][CH:7]=1
Reactant: Cc1cccc2c1NCCC2
Reactant: O=C(O)CSc1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c1N(C(=O)CSc1ccc(Cl)cn1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of (5-chloro-pyridin-2-ylsulfanyl)-acetic acid (15, 0.27 g, 1.3 mmol) in dry CH2Cl2 (10 mL) and DMF (2 mL) at 0° C. was added HATU (0.5 g, 1.3 mmol) and reaction mixture was stirred for 30 min at ambient temperature. Then the reaction mixture was cooled to 0° C. and neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) was added via syringe followed by addition of DIPEA, (0.69 mL, 3.9 mmol). The reaction mixture was allowed to warm to room temperature over 18 h. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 90 mg of the target 16 as a white solid in 20% yield. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (20%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.33; H, 5.06; N, 8.36; Cl. 10.67; S, 9.56.