Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=[CH:5][CH:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:12][CH:1]([C:3]1[N:8]2[N:9]=[CH:10][N:11]=[C:7]2[N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccnc2ncnn12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccnc2ncnn12

Procedure:
A mixture of 7-ethyl-1,2,4-triazolo[1,5-a]pyrimidine (10.5 g), N-bromosuccinimide (12.63 g), dibenzoylperoxide (0.3 g) and tetrachloromethane (270 ml) was heated under reflux for 5 hours with stirring. The mixture was filtered and a crude product was obtained by evaporation of the solvent from the filtrate. This was purified by recrystallisation from tetrachloromethane to give 7-(1-bromoethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 10.8 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([NH:20]C2C=C(C(OC)=S)SC=2C)[CH:17]=[CH:18][CH:19]=1)[CH3:13].C[Al](C)C.[NH4+].[Cl-]>>[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([NH:20][C:4]2[CH:5]=[C:6]([C:8]([NH2:10])=[NH:9])[S:7][C:3]=2[S:2][CH3:1])[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: CSc1ccc(C(=N)N)s1
Reactant: COC(=S)c1cc(Nc2cccc(C(C)C)c2)c(C)s1
Agent: C[Al](C)C
Agent: [Cl-]
Agent: [NH4+]
Product: CSc1sc(C(=N)N)cc1Nc1cccc(C(C)C)c1

Procedure:
4-{[3-Methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine: Using a procedure similar to Example 154, step (b), 22.6 mg (0.07 mmol) of methyl 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxylate was allowed to react with 8 equiv (0.56 mmol) of the AlMe3/NH4Cl reagent to afford 18.9 mg (78.8%) of) 4-{[3-(methylethyl)phenyl]amino}-5-methylthiothiophene-2-carboxamidine. 1H NMR (DMSO-d6, 400 MHz) δ 1.18 (d, 6H, J=9.2 Hz), 2.51 (s, 3H), 2.81 (m, 1H), 6.71-6.77 (m, 2H), 6.85 (s, 1H), 7.14 (m, 1H), 7.98 (s, 1H), 8.32 (s, 1H), 8.88 (bs, 2H), 9.23 (bs, 2H). Mass spectrum (ESI, m/z): Calcd. for C15H19N3S2, 306.11 (M+H), found 306.2.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1)([O-])=O.[OH-].[Na+].[H][H]>[Ni]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14](=[O:18])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:19])[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O

Procedure:
A 160 ml. electromagnetically stirred autoclave was charged with 2.53 g (0.01 mole) of 2-nitroanthraquinone, 52 g (0.052 mole) of a 4% aqueous solution of sodium hydroxide, and 0.07 g of Raney nickel, and the 2-nitroanthraquinone was hydrogenated at room temperature and a pressure of 6 to 3 Kg/cm2.G with stirring. The reaction was stopped in 6 hours with the absorption of 0.04 mole of hydrogen. The inside of the reactor was purged with nitrogen, and the reaction mixture was filtered in a stream of nitrogen to separate the catalyst. The filtrate was oxidized with air with stirring at 20° to 30° C. for 2 hours to afford 2.1 g of high purity 2-aminoanthraquinone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]([O:30]C)=[O:29])=[O:18])[CH:13]=2)[CH:7]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([NH:38][C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:40]=1[F:46])=[O:37])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[C:28]([OH:30])=[O:29])=[O:18])[CH:13]=2)[CH:7]=1
Reactant: COC(=O)C1CCCN1CCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCCC5C(=O)O)c[nH]4)c3)cc2F)c1
Temperature: 50 °C

Procedure:
To a stirred suspension of methyl 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylate (100 mg, 0.16 mmol) in 1 ml of MeOH was added 0.2N NaOH solution (2 ml, 0.4 mmol). The mixture was heated at 50° C. for 16 hours and cooled to room temperature. 1M HCl was added dropwise with vigorous stirring until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-2-carboxylic acid as white solid. Yield: 72 mg, 73%.
Reaction SMILES: [C:1](N1C(N)=C(C2C=CN=CC=2)C=N1)(=N)N.[C:16]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[CH:21]=[N:20]1)(=[NH:18])[NH2:17]>>[NH2:18][C:16]1[N:19]2[N:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][N:26]=3)=[C:23]2[N:24]=[CH:1][N:17]=1
Reactant: N=C(N)n1ncc(-c2ccncn2)c1N
Reactant: N=C(N)n1ncc(-c2ccncc2)c1N
Product: Nc1ncnc2c(-c3ccncn3)cnn12
Yield: 80 %

Procedure:
By replacing the 1-amidino-4-(4-pyridyl)-5-aminopyrazole in Example 1C with an equivalent quantity of 1-amidino-4-(4-pyrimidinyl)-5-aminopyrazole there is obtained an 80% yield of 4-amino-8-(4-pyrimidinyl)-pyrazolo-[1,5-a][1,3,5]triazine which separates from boiling dimethylformamide in crystals melting at about 340° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])=[O:10])=[CH:4][CH:3]=1.[Br:19]Br>C1C=CC=CC=1>[Br:19][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[O:10]
Reactant: O=C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1Cl)C(Br)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Part C: To a solution of 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone (5.00 gram, 15 mmol) in benzene (50 mL) is dropwise added bromine (0.75 mL, 15 mmol) and the resulting solution is stirred for 4 hours at room temperature and concentrated in vacuo. Dichloromethane is added and the resulting solution is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 2-bromo-2-(4-bromophenyl)-1-(2,4-dichlorophenyl)ethanone as an oil (5.96 gram, 94% yield).
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:12]([O:24][CH3:25])=[C:11]([O:26][CH3:27])[C:10]([O:28][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)=[CH:9][C:8]=2[CH2:7][CH2:6]1)=[O:3].[OH-].[Na+]>P(=O)(O)(O)O.CO>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([S:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([OH:28])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc2c(c1OC)-c1ccc(SC)c(=O)cc1C(NC(C)=O)CC2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(O)cc2c(c1OC)-c1ccc(SC)c(=O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A solution of thiocolchicoside (2.3 g, 3.96 mmol) in phosphoric acid (85-88%, 65 ml) after dissolving by heating, was stirred at room temperature for overnight. The TLC analysis showed the absence of thiocolchicoside in the reaction mixture, (one small drop of reaction mixture was diluted with MeOH (0.5 ml) and applied to a TLC plate and run in solvent system A). The reaction mixture was poured on ice, adjusted to pH 5 by the addition of 15% aqueous NaOH solution, followed by several extractions with CH2Cl2 (4×25 ml). The combined organic layers were dried (Na2SO4) and evaporated to afford a residue, which was crystallized with acetone to afford 3-demethylthiocolchicine as a yellow solid (1.5 g, 93%), mp 316° C.; [α]D25 =-251° (c 0.21, CHCl3); IR (CHCl3) cm-1 ; 3440 (OH); CIMS: m/e 402 (M+ +1); Anal. Calcd. for C21H23NO5S: C, 62.82; H, 5.77; N, 3.48; S, 7.98. Found C, 63.09; H, 5.86; N, 3.26; S, 8.25%.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([N:18]([CH2:19][CH3:20])[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:17]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CCNCC
Agent: Cl
Solvent: O
Product: CCN(CC)c1ccc(S(C)(=O)=O)cc1C(=O)O

Procedure:
3.0 g of 2-fluoro-5-methanesulfonyl-benzoic acid (CA 247569-56-8; WO200501453) was dissolved in 30 ml of diethylamine and refluxed overnight. The reaction mixture was diluted with water, acidified by addition of diluted hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and concentrated to give the title compound as a slightly brownish solid. MS (m/e): 272.1 (M+H+; 100%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:9](Cl)(Cl)=[O:10]>CCOCC>[Cl:1][C:2]1[C:7]([N:8]=[S:9]=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=S=Nc1cccnc1Cl
Reaction time: 15 h

Procedure:
A solution of 2-chloro-3-aminopyridine (12.9 g, 0.1 m) and thionyl chloride (5.5 g, 0.05 m) in Et2O (100 ml) is heated at reflux with stirring. After 15 hours, the 2-chloro-3-aminopyridine HCl is filtered off and the solution concentrated to dryness to yield 2-chloro-3-thionylaminopyridine (1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=2[N+:15]([O-])=O)=[CH:5][CH:4]=1.[Cl-].[NH4+]>C(O)C.C1COCC1.O>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][S:8][C:9]2[CH:10]=[C:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][C:14]=2[NH2:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(SCc2ccc(OC)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(SCc2ccc(OC)cc2)c1
Yield: 80.3 %

Procedure:
Under stirring, a solution of ethyl 3-(4-methoxybenzylthio)-4-nitrophenylacetate (3.33 g, 9.92 mmol), ammonium chloride (542 mg, 10.1 mmol) and reduced iron powder (2.57 g, 46.1 mmol) in ethanol/THF/water (2:2:1, 75 ml) was heated and refluxed for 1.5 hours. After the reaction mixture was cooled, the insoluble matter was filtered off. The filtrate was distilled under reduced pressure to remove the solvent. The residue was neutralized by pouring therein a saturated aqueous solution of sodium bicarbonate, followed by extraction with a chloroform-methanol mixture. The extract was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform-ethyl acetate (20:1) eluate fractions, ethyl 3-(4-methoxybenzylthio)-4-aminophenylacetate (2.64 g, 86%) was obtained as a yellow oil.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1S(C)(=O)=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N>O>[CH2:11]([N:18]1[C:22]2[C:23](=[O:34])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nc2ccn(Cc3ccccc3)c(=O)c2n1Cc1ccccc1
Reactant: C1CNCCN1
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2c(ccn1Cc1ccccc1)nc(N1CCNCC1)n2Cc1ccccc1
Temperature: 150 °C
Reaction time: 24 h
Yield: 5.5 %

Procedure:
660 mg (11 mmol) of glacial acetic acid were added dropwise to 860 mg (10 mmol) of piperazine with cooling, then 180 mg of 3,5-dibenzyl-2-methanesulphonyl-3,5-dihydro-imidazo[4,5-c]pyridin-4-one (crude product from Example 3 h) were added and the mixture was stirred for 24 hours at 150° C. After cooling approx. 10 ml of water were added, the mixture was made alkaline with concentrated ammonia solution and the mixture was extracted three times with 5 ml of dichloromethane. The extracts were dried over sodium sulphate and concentrated by evaporation. The crude product thus obtained was purified by column chromatography (silica gel; eluant:petroleum ether with 20–60% ethyl acetate).
Reaction SMILES: COC1C2C(=C(OC)C=CC=2)C(OC)=CC=1C([CH:19]1[CH2:25][CH2:24][C:23]2([C:27]3([CH3:32])OCC[O:28]3)[CH2:26][CH:20]1[C:21](=[O:33])[O:22]2)=O.Cl.[CH3:35][OH:36]>>[CH3:35][O:36][C:21]([CH:20]1[CH2:26][C:23]([C:27](=[O:28])[CH3:32])([OH:22])[CH2:24][CH2:25][CH2:19]1)=[O:33]
Reactant: COc1c(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)cc(OC)c2c(OC)cccc12
Reactant: CO
Agent: Cl
Product: COC(=O)C1CCCC(O)(C(C)=O)C1

Procedure:
1.6 g of 2-(1,4,5-trimethoxy-2-naphthylcarbonyl)-5-(2-methyl-dioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one, prepared as described in Example 4, was dissolved in methanol and treated at room temperature for 1 hour with a 1N solution of hydrogen chloride in anhydrous methanol. After evaporating off the solvent, there was obtained in almost quantitative yield 1.5 g of 1-1,4,5-trimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane (X, R=OCH3). m/z 444 (M+.); IR (film): 3460 cm-1 (OH), 1730 cm-1 (C=O ester, 1710 cm-1 (C=O ketone) and 1665 cm-1 (C=O benzylic ketone). PMR (CDCl3): inter alia 2.3 (s, CH3CO), 3.75-4.05 (s, four OCH3), 6.8 (s, aromatic H) and 6.85-8.0 (m, three aromatic H). 1.5 g of this compound was dissolved in 15 mo of trifluoroacetic acid and refluxed with 1.4 ml of pyridine-borane complex. After removal of the solvent, the residue was treated with a 10% aqueous solution of sodium hydroxide. After mild acidification the free acid was extracted with ethyl acetate. The solvent was evaporated off and the residue was directly treated with an ethereal solution of phenyldiazomethane to give the title product. This was purified by chromatography: m/z 508 (M+.); PMR (CDCl3): inter alia 1.25 (d, CH3 --CH), 3.70-3.95 (s, three OCH3), 5.15 (d, CH2Ph) and 6.4-8.1 (m, nine aromatic H).
Reaction SMILES: [Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][N:13]([CH3:18])[CH2:12][CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2
Reactant: Clc1c2c(nc3ccnn13)CCNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCc2nc3ccnn3c(Cl)c2CC1

Procedure:
To 20.0 g (77.2 mmol) 10-Chloro-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 200 mL buffer (pH=5) 6.4 mL formaldehyde (37% in water, 84.9 mmol) and 19.7 g sodium triacetoxyborohydride (93.0 mmol) were added under cooling with ice and stirring was continued over night. The mixture was then diluted at 0° C. with K2CO3-solution (15% in water) and extracted with ethyl acetate. The organic layers were combined, dried (Na2SO4) and concentrated. The residue was then purified by column chromatography (silica, EtOAc/MeOH/NH4OH=9:1:0.1) to give the desired product.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-n2cncn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,4-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[C:9]([CH:10]=[N:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:8][C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)([O-:3])=[O:2]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: NC1CCCCC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(C=NC2CCCCC2)c([N+](=O)[O-])cc1OC
Yield: 80.4 %

Procedure:
A suspension of 42.2 g (0.2 mole) of 6-nitroveratraldehyde, 19.8 g (0.2 mole) cyclohexylamine, 1.0 ml. glacial acetic acid, and 1.25 l. ethanol was stirred and refluxed for 5 min., cooled, and filtered. The solid was washed with 100 ml. cold ethanol and air dried to give 47.0 g (80%) of the product, m.p. 160°-161°.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1.Br[CH2:29][C:30]([O:32][C:33](C)(C)[CH3:34])=[O:31]>C1COCC1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:21][C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1)[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCc1cnccn1
Temperature: 2.5 °C
Yield: 49.9 %

Procedure:
Butyl lithium (2.5M in hexane-2560 mL) was added within 2 hours into a 10 L flask charged with THF (3350 mL) and diisopropylamine (658 g) while the temperature was maintained at 0-5° C. with an ice bath. The LDA solution was then precooled to −50° C. and a mixture of methylpyrazine (606 g) and THF (590 mL) was added within 2 hours under vigorous stirring at −40 to −30° C. The deep red anion solution is then pumped to a cooled (−60° C.) mixture of tert-butyl bromoacetate (1255 g) and THF (3360 mL) in a 20 L reactor. During the addition of the anion solution, the temperature in the reaction vessel did not exceed −55° C. After the addition, the mixture is stirred for further 30 min at −55° C. and then transferred to a 30 L reactor (the transesterification and removal of solvents can be done for two runs at once). A solution of sodium ethylate (142 g) dissolved in EtOH (2200 mL) was then added to the orange mixture and about 12 L of solvents were distilled off until a temperature of 80° C. was reached in the distillation head and 100° C. in the boiling liquid. The mixture was cooled to approximately 30° C. and then toluene (840 mL), AcOEt (840 mL), and water (1180 mL) were added. After separation of the phases, the organic layer was extracted three times with AcOEt (420 mL) and toluene (170 mL) each. The combined organic phases were then concentrated in vacuo and the residue was distilled over a Vigreux column (bp 115 to 130° C. @ 0.07 mbar) giving the title compound (579 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([N:17]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]2)[C:3]=1[NH:25][C:26](=O)[C:27]([CH3:30])([CH3:29])[CH3:28].[OH-].[Na+]>C(O)(=O)C>[C:27]([C:26]1[NH:25][C:3]2[C:4]([N:17]3[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18]3)=[C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]([CH3:10])=[C:7]([C:8]#[N:9])[C:2]=2[N:1]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1c(C#N)c(N)c(NC(=O)C(C)(C)C)c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2[nH]c(C(C)(C)C)nc2c1C#N

Procedure:
An acetic acid (5 ml) solution of N-[4-amino-5-cyano-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-methylbiphenyl-3-yl]-2,2-dimethylpropionamide (I-270) (300 mg, 0.72 mmol) was heated at 80° C. for 2.5 hours. After cooling, the reaction solution was poured into aqueous sodium hydroxide solution (6.7 M, 15 ml).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:49]1[C:53]2=[CH:54][N:55]=[CH:56][CH:57]=[C:52]2[C:51](Br)=[CH:50]1)=O)(C)(C)C>S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:41][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:51]4[C:52]5[C:53](=[CH:54][N:55]=[CH:56][CH:57]=5)[NH:49][CH:50]=4)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:40])[C:37]([NH2:39])=[O:38]
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2ccncc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4c[nH]c5cnccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 10 %

Procedure:
To a mixture of 2-[4-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-isobutyramide (275 mg, 0.396 mmol), 3-bromo-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (177 mg, 0.596 mmol), copper(I) thiophene-2-carboxylate (76 mg, 0.40 mmol), and Pd(PPh3)4 (46 mg, 0.040 mmol) was added 1,4-dioxane (2 mL). The reaction vessel was evacuated and back filled with argon under sonication. The reaction mixture was heated in the microwave at 140° C. for 20 minutes. The reaction mixture volume was doubled with a solution of 10% MeOH in DCM. The mixture was filtered through a plug of solka floc and the filtrate was concentrated. The green residue was triturated with hexane and dried in vacuo. The light green solid was purified by flash chromatography (silica, 0-10% of a 9:1 MeOH/NH4OH solution in DCM) to give 137 (20.6 mg, 10%) as an off-white solid. LCMS: M+H+=521. 1H-NMR (300 MHz, DMSO-d6): δ 12.0 (s, 1H), 8.79 (s, 1), 8.39 (d, 1H), 8.37 (d, 1H), 8.23 (d, 1H), 7.35 (s, 1H), 7.07 (d, 1H), 6.95 (d, 1H), 3.97 (m, 4H), 3.83 (m, 6), 2.55 (m, 4H), 2.46 (m, 4H), 1.08 (s, 6H)
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:20][CH2:19]2)[C:11]1=[O:21].Cl>CN(C)C=O>[O:8]=[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:21])[C:12]12[CH2:20][CH2:19]1)[CH2:6][CH3:7]
Reactant: CCC(=O)Cl
Reactant: O=C1Nc2ccccc2C12CC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc2c(c1)C1(CC1)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A slurry was made from 7.5 ml of dimethylformamide and 45.5 g of anhydrous aluminum chloride. The temperature rose to 40° C. and 2.97 ml of propionyl chloride and 5.43 g of spiro[cyclopropane-1,3'-[3H]-indol]-2'(1'H)-one were added. The mixture was stirred for 2 hours at 70° C. and was slowly poured into a mixture of ice and 50 ml of concentrated hydrochloric acid. After cooling overnight, the resulting precipitate was recovered by filtration. Crystallization from ethyl acetate provided 4.9 grams of the desired subtitle intermediate, m.p. 183°-185° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH:31]1[CH2:36][CH2:35][CH:34]([NH:37]C(=O)OC(C)(C)C)[CH2:33][CH2:32]1>>[NH2:37][CH:34]1[CH2:35][CH2:36][N:31]([CH2:28][C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:30])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCC(N)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 63 using product of Example 59 step iii) and piperidin-4-yl-carbamic acid, tert-butyl ester.